PHYSIOLOGICAL PSYCHOLOGY - University of Calicutuniversityofcalicut.info/SDE/CP1 C01...

PHYSIOLOGICAL PSYCHOLOGY

B.Sc. in Counselling Psychology

Complementary Course

I Semester(2011 Admission onwards)

UNIVERSITY OF CALICUTSCHOOL OF DISTANCE EDUCATIONCalicut University P.O. Malappuram, Kerala, India 673 635











School of Distance Education

Physiological Psychology - I Semester 2

UNIVERSITY OF CALICUTSCHOOL OF DISTANCE EDUCATIONB.Sc in Counselling Psychology

I SemesterComplimentary Course

PHYSIOLOGICAL PSYCHOLOGYPrepared andscrutinised by : Prof. (Dr.) C. JayanDepartment of PsychologyUniversity of CalicutLayout: Computer Section, SDE©

Reserved



CONTENTS PAGE

MODULE 1 Introduction-The three approaches tobrain

5 - 12

MODULE 2 Cellular Basis of Behaviour 13 - 47

MODULE 3 The Neuron 48 - 90



MODULE 1

Introduction

THE THREE APPROACHES TO BRAIN

Ablation

Ablation means removal of material from the surface of an object by vaporization, chipping, orother erosive processes. The term occurs in spaceflight associated with atmospheric reentry, inglaciology, medicine, and passive fire protection.

Spaceflight

In spacecraft design, ablation is used to both cool and protect mechanical parts and/or payloads thatwould otherwise be damaged by extremely high temperatures. Two principal applications are heatshields for spacecraft entering a planetary atmosphere from space and cooling of rocket enginenozzles. Examples include the Apollo Command Module that protected astronauts from the heat ofatmospheric reentry and the Kestrel second stage rocket engine designed for exclusive use in anenvironment of space vacuum since no heat convection is possible.

In a basic sense, ablative material is designed to slowly burn away in a controlled manner, so thatheat can be carried away from the spacecraft by the gases generated by the ablative process; whilethe remaining solid material insulates the craft from superheated gases. There is an entire branch ofspaceflight research involving the search for new fireproofing materials to achieve the best ablativeperformance; this function is critical to protect the spacecraft occupants and payload fromotherwise excessive heat loading. The same technology is used in some passive fire protectionapplications, in some cases by the same vendors, who offer different versions of these fireproofingproducts, some for aerospace and some for structural fire protection.

Glaciology

In glaciology, ablation refers to processes that remove snow and ice from a glacier. Ablation mayrefer to the melting of snow or ice that runs off the glacier, evaporation, sublimation, calving, orremoval of snow by wind.

Medicine

In medicine, ablation is the same as removal of a part of biological tissue, usually by surgery.Surface ablation of the skin (dermabrasion, also called resurfacing because it induces regeneration)can be carried out by chemicals (which cause peeling) or by lasers. Its purpose is to remove skinspots, aged skin, wrinkles, thus rejuvenating it. Surface ablation is also employed in otolaryngologyfor several kinds of surgery, such as for snoring. Ablation therapy using radio frequency waves onthe heart is used to cure a variety of cardiac arrhythmia such as supraventricular tachycardia,Wolff-Parkinson-White syndrome (WPW), ventricular tachycardia, and more recently asmanagement of atrial fibrillation. The term is often used in the context of laser ablation, a processin which a laser dissolves a material's molecular bonds. For a laser to ablate tissues, the powerdensity or fluence must be high, otherwise thermocoagulation occurs, which is simply thermalvaporization of the tissues.



Rotoablation is a type of arterial cleansing that consists of inserting a tiny, diamond-tipped, drill-like device into the affected artery to remove fatty deposits or plaque. The procedure is used in thetreatment of coronary heart disease to restore blood flow.

Radio frequency ablation is a method of removing aberrant tissue from within the body viaminimally invasive procedures. i.e.RF ablation in an Electrophysiology study to remove cells thatare issuing abnormal electrical activity leading to arrhythmia.

Bone marrow ablation is a process whereby the human bone marrow cells are eliminated inpreparation for a bone marrow transplant. This is performed using high-intensity chemotherapy andtotal body irradiation. As such it has nothing to do with the vaporization techniques described in therest of this article.

Ablation of brain tissue is used for treating certain neurological disorders, particularly Parkinson'sdisease, and sometimes for psychiatric disorders as well.

Recently, some researchers reported successful results with genetic ablation. In particular, geneticablation is potentially a much more efficient method of removing unwanted cells, such as tumorcells, because large numbers of animals lacking specific cells could be generated. Geneticallyablated lines can be maintained for a prolonged period of time and shared within the researchcommunity. Researchers at Columbia University report of reconstituted caspases combined from C.elegans and humans, which maintain a high degree of target specificity. The genetic ablationtechniques described could prove useful in battling cancer.

Biology

Ablation in biology can refer to genetic or cell ablation, for example. Genetic ablation describes agene that has been silenced. It can be used on purpose in experiments where scientists can observethe effect of genetic silencing. Cell ablation is where individual cells are destroyed for experimentalreasons.

Laser ablation

Laser ablation is greatly affected by the nature of the material and its ability to absorb energy,therefore the wavelength of the ablation laser should have a minimum absorption depth.

Surface ablation of the cornea for several types of eye refractive surgery is now common, using anexcimer laser system (LASIK and LASEK). Since the cornea does not grow back, laser is used toremodel the cornea refractive properties to correct refraction errors, such as astigmatism, myopia,and hyperopia. Laser ablation is also used to remove part of the uterine wall in women withmenstruation and adenomyosis problems in a process called endometrial ablation.

Passive fire protection

Firestopping and fireproofing products can be ablative in nature. This can mean endothermicmaterials, or merely materials that are sacrificial and become "spent" over time while exposed tofire such as silicone firestop products. Given sufficient time under fire or heat conditions, these



products char away, crumble, and disappear. The idea is to put enough of this material in the way ofthe fire that a level of fire-resistance rating can be maintained, as demonstrated in a fire test.Ablative materials usually have a large concentration of organic matter[citation needed] that isreduced by fire to ashes. In the case of silicone, organic rubber surrounds very finely divided silicadust (up to 380 m² of combined surface area of all the dust particles per gram of this dust[citationneeded]). When the organic rubber is exposed to fire it burns to ash and leaves behind the silicadust with which the product started.

Marine Surface Coatings

Antifouling paints and other related coatings are routinely used to prevent the buildup ofmicroorganisms and other animals, such as barnacles for the bottom hull surfaces of recreational,commercial and military sea vessels. Ablative paints are often utilized for this purpose to preventthe dilution or deactivation of the antifouling agent. Over time, the paint will slowly decompose inthe water, exposing fresh antifouling compounds on the surface. Engineering the antifouling agentsand the ablation rate can produce long-lived protection from the deleterious effects of biofouling.

Stimulation

Stimulation is the action of various agents (stimuli) on muscles, nerves, or a sensory end organ, bywhich activity is evoked; especially, the nervous impulse produced by various agents on nerves, ora sensory end organ, by which the part connected with the nerve is thrown into a state of activity.

The word is also often used metaphorically. For example, an interesting or fun activity can bedescribed as "stimulating", regardless of its physical effects on nerves.

It is also used in simulation technology to describe a synthetically-produced signal that triggers(stimulates) real equipment, see below.

Overview

Stimulation in general refers to how organisms perceive incoming stimuli. As such it is part ofthe stimulus-response mechanism. Simple organisms broadly react in three ways to stimulation: toolittle stimulation causes them to stagnate, too much to die from stress or inability to adapt, and amedium amount causes them to adapt and grow as they overcome it. Similar categories or effectsare noted with psychological stress with people. Thus, stimulation may be described as howexternal events provoke a response by an individual in the attempt to cope.

Use in Simulators and Simulation Technology Stimulation describes a type of simulationwhereby artificially-generated signals are fed to real equipment or software in order to Stimulate itto produce the result required for training, maintenance or for R&D. The real equipment can beradar, sonics, instruments, software and so on. In some cases the Stimulation equipment can becarried in the real platform or carriage vehicle (that is the Ship, AFV or Aircraft) and be used forso-called "embedded training" during its operation, by the generation of simulated scenarios whichcan be dealt with in a realistic manner by use of the normal controls and displays. In the overalldefinition of simulation, the alternative method is called "emulation" which is the simulation ofequipment by entirely artificial means by physical and software modelling.



Over-stimulation

Psychologically, it is possible to become habituated to a degree of stimulation, and then find ituncomfortable to have significantly more or less. Thus one can become used to an intense life, ortelevision, and suffer withdrawal when they are removed, from lack of stimulation, and it ispossible to also be unhappy and stressed due to additional abnormal stimulation.

It is hypothesized and commonly believed by some that psychological habituation to a high level ofstimulation ("over-stimulation") can lead to psychological problems. For example, some foodadditives can result in children becoming prone to over-stimulation, and ADHD is, theoretically, acondition in which over-stimulation is a part. It is also hypothesized that long term over-stimulationcan result eventually in a phenomenon called "adrenal exhaustion" over time, but this is notmedically accepted or proven at this time.

What is sure is that ongoing, long term stimulation, can for some individuals prove harmful, and amore relaxed and less stimulated life may be beneficial.

Recording

Recording is a process of capturing data or translating information to a format stored on a storagemedium often referred to as a record.

Ways of recording text suitable for direct reading by humans includes writing it on paper. Otherforms of data storage are easier for automatic retrieval, but humans need a tool to read them.Printing a text stored in a computer allows keeping a copy on the computer and having also a copythat is human-readable without a tool.

Technology continues to provide and expand means for human beings to represent, record andexpress their thoughts, feelings and experiences.

New Techniques in this Field

History

In 1918 the American neurosurgeon Walter Dandy introduced the technique of ventriculography.X-ray images of the ventricular system within the brain were obtained by injection of filtered airdirectly into one or both lateral ventricles of the brain. Dandy also observed that air introduced intothe subarachnoid space via lumbar spinal puncture could enter the cerebral ventricles and alsodemonstrate the cerebrospinal fluid compartments around the base of the brain and over its surface.This technique was called pneumoencephalography.

In 1927 Egas Moniz introduced cerebral angiography, whereby both normal and abnormal bloodvessels in and around the brain could be visualized with great precision.

In the early 1970s, Allan McLeod Cormack and Godfrey Newbold Hounsfield introducedcomputerized axial tomography (CAT or CT scanning), and ever more detailed anatomic images ofthe brain became available for diagnostic and research purposes. Cormack and Hounsfield won the1979 Nobel Prize for Physiology or Medicine for their work. Soon after the introduction of CAT in



the early 1980s, the development of radioligands allowed single photon emission computedtomography (SPECT) and positron emission tomography (PET) of the brain.

More or less concurrently, magnetic resonance imaging (MRI or MR scanning) was developed byresearchers including Peter Mansfield and Paul Lauterbur, who were awarded the Nobel Prize forPhysiology or Medicine in 2003. In the early 1980s MRI was introduced clinically, and during the1980s a veritable explosion of technical refinements and diagnostic MR applications took place.Scientists soon learned that the large blood flow changes measured by PET could also be imagedby the correct type of MRI. Functional magnetic resonance imaging (fMRI) was born, and since the1990s, fMRI has come to dominate the brain mapping field due to its low invasiveness, lack ofradiation exposure, and relatively wide availability. As noted above fMRI is also beginning todominate the field of stroke treatment.

In early 2000s the field of neuroimaging reached the stage where limited practical applications offunctional brain imaging have become feasible. The main application area is crude forms of brain-computer interface.

Brain imaging techniques

Computed axial tomography

Computed tomography (CT) or Computed Axial Tomography (CAT) scanning uses a series ofx-rays of the head taken from many different directions. Typically used for quickly viewing braininjuries, CT scanning uses a computer program that performs a numerical integral calculation (theinverse Radon transform) on the measured x-ray series to estimate how much of an x-ray beam isabsorbed in a small volume of the brain. Typically the information is presented as cross sections ofthe brain.

In approximation, the denser a material is, the whiter a volume of it will appear on the scan (just asin the more familiar "flat" X-rays). CT scans are primarily used for evaluating swelling from tissuedamage in the brain and in assessment of ventricle size. Modern CT scanning can providereasonably good images in a matter of minutes.

Diffuse optical imaging

Diffuse optical imaging (DOI) or diffuse optical tomography (DOT) is a medical imaging modalitywhich uses near infrared light to generate images of the body. The technique measures the opticalabsorption of haemoglobin, and relies on the absorption spectrum of haemoglobin varying with itsoxygenation status.

Event-related optical signal

Event-related optical signal (EROS) is a brain-scanning technique which uses infrared light throughoptical fibers to measure changes in optical properties of active areas of the cerebral cortex.Whereas techniques such as diffuse optical imaging (DOT) and near infrared spectroscopy (NIRS)measure optical absorption of haemoglobin, and thus are based on blood flow, EROS takesadvantage of the scattering properties of the neurons themselves, and thus provides a much moredirect measure of cellular activity. EROS can pinpoint activity in the brain within millimeters



(spatially) and within milliseconds (temporally). Its biggest downside is the inability to detectactivity more than a few centimeters deep. EROS is a new, relatively inexpensive technique that isnon-invasive to the test subject. It was developed at the University of Illinois at Urbana-Champaignwhere it is now used in the Cognitive Neuroimaging Laboratory of Dr. Gabriele Gratton and Dr.Monica Fabiani.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) uses magnetic fields and radio waves to produce high qualitytwo- or three-dimensional images of brain structures without use of ionizing radiation (X-rays) orradioactive tracers. During an MRI, a large cylindrical magnet creates a magnetic field around thehead of the patient through which radio waves are sent. When the magnetic field is imposed, eachpoint in space has a unique radio frequency at which the signal is received and transmitted (Preuss).Sensors read the frequencies and a computer uses the information to construct an image. Thedetection mechanisms are so precise that changes in structures over time can be detected.

Using MRI, scientists can create images of both surface and subsurface structures with a highdegree of anatomical detail. MRI scans can produce cross sectional images in any direction fromtop to bottom, side to side, or front to back. The problem with original MRI technology was thatwhile it provides a detailed assessment of the physical appearance, water content, and many kindsof subtle derangements of structure of the brain (such as inflammation or bleeding), it fails toprovide information about the metabolism of the brain (i.e. how actively it is functioning) at thetime of imaging. A distinction is therefore made between "MRI imaging" and "functional MRIimaging" (fMRI), where MRI provides only structural information on the brain while fMRI yieldsboth structural and functional data.

Functional magnetic resonance imaging

Axial MRI slice at the level of the basal ganglia, showing fMRI BOLD signal changes overlayed inred (increase) and blue (decrease) tones.

Functional magnetic resonance imaging (fMRI) relies on the paramagnetic properties ofoxygenated and deoxygenated hemoglobin to see images of changing blood flow in the brainassociated with neural activity. This allows images to be generated that reflect which brainstructures are activated (and how) during performance of different tasks.

Most fMRI scanners allow subjects to be presented with different visual images, sounds and touchstimuli, and to make different actions such as pressing a button or moving a joystick. Consequently,fMRI can be used to reveal brain structures and processes associated with perception, thought andaction. The resolution of fMRI is about 2-3 millimeters at present, limited by the spatial spread ofthe hemodynamic response to neural activity. It has largely superseded PET for the study of brainactivation patterns. PET, however, retains the significant advantage of being able to identifyspecific brain receptors (or transporters) associated with particular neurotransmitters through itsability to image radiolabelled receptor "ligands" (receptor ligands are any chemicals that stick toreceptors).

As well as research on healthy subjects, fMRI is increasingly used for the medical diagnosis ofdisease. Because fMRI is exquisitely sensitive to blood flow, it is extremely sensitive to early



changes in the brain resulting from ischemia (abnormally low blood flow), such as the changeswhich follow stroke. Early diagnosis of certain types of stroke is increasingly important inneurology, since substances which dissolve blood clots may be used in the first few hours aftercertain types of stroke occur, but are dangerous to use afterwards. Brain changes seen on fMRI mayhelp to make the decision to treat with these agents. With between 72% and 90% accuracy wherechance would achieve 0.8%, fMRI techniques can decide which of a set of known images thesubject is viewing.

Electroencephalography

Electroencephalography (EEG) is an imaging technique used to measure the electric fields in thebrain via electrodes placed on the scalp of a human. EEG offers a very direct measurement ofneural electrical activity with very high temporal resolution but relatively low spatial resolution.

Magnetoencephalography

Magnetoencephalography (MEG) is an imaging technique used to measure the magnetic fieldsproduced by electrical activity in the brain via extremely sensitive devices such as superconductingquantum interference devices (SQUIDs). MEG offers a very direct measurement neural electricalactivity (compared to fMRI for example) with very high temporal resolution but relatively lowspatial resolution. The advantage of measuring the magnetic fields produced by neural activity isthat they are not distorted by surrounding tissue, unlike the electric fields measured by EEG(particularly the skull and scalp).

There are many uses for the MEG, including assisting surgeons in localizing a pathology, assistingresearchers in determining the function of various parts of the brain, neurofeedback, and others.

Positron emission tomography

Positron emission tomography (PET) measures emissions from radioactively labeled metabolicallyactive chemicals that have been injected into the bloodstream. The emission data are computer-processed to produce 2- or 3-dimensional images of the distribution of the chemicals throughout thebrain. The positron emitting radioisotopes used are produced by a cyclotron, and chemicals arelabeled with these radioactive atoms. The labeled compound, called a radiotracer, is injected intothe bloodstream and eventually makes its way to the brain. Sensors in the PET scanner detect theradioactivity as the compound accumulates in various regions of the brain. A computer uses thedata gathered by the sensors to create multicolored 2- or 3-dimensional images that show where thecompound acts in the brain. Especially useful are a wide array of ligands used to map differentaspects of neurotransmitter activity, with by far the most commonly used PET tracer being alabeled form of glucose (see FDG).

The greatest benefit of PET scanning is that different compounds can show blood flow and oxygenand glucose metabolism in the tissues of the working brain. These measurements reflect the amountof brain activity in the various regions of the brain and allow to learn more about how the brainworks. PET scans were superior to all other metabolic imaging methods in terms of resolution andspeed of completion (as little as 30 seconds), when they first became available. The improvedresolution permitted better study to be made as to the area of the brain activated by a particular task.The biggest drawback of PET scanning is that because the radioactivity decays rapidly, it is limited



to monitoring short tasks. Before fMRI technology came online, PET scanning was the preferredmethod of functional (as opposed to structural) brain imaging, and it still continues to make largecontributions to neuroscience.

PET scanning is also used for diagnosis of brain disease, most notably because brain tumors,strokes, and neuron-damaging diseases which cause dementia (such as Alzheimer's disease) allcause great changes in brain metabolism, which in turn causes easily detectable changes in PETscans. PET is probably most useful in early cases of certain dementias (with classic examples beingAlzheimer's disease and Pick's disease) where the early damage is too diffuse and makes too littledifference in brain volume and gross structure to change CT and standard MRI images enough tobe able to reliably differentiate it from the "normal" range of cortical atrophy which occurs withaging (in many but not all) persons, and which does not cause clinical dementia.

Single photon emission computed tomography

Single photon emission computed tomography (SPECT) is similar to PET and uses gamma rayemitting radioisotopes and a gamma camera to record data that a computer uses to construct two- orthree-dimensional images of active brain regionsSPECT relies on an injection of radioactive tracer,which is rapidly taken up by the brain but does not redistribute. Uptake of SPECT agent is nearly100% complete within 30 – 60s, reflecting cerebral blood flow (CBF) at the time of injection.These properties of SPECT make it particularly well suited for epilepsy imaging, which is usuallymade difficult by problems with patient movement and variable seizure types. SPECT provides a"snapshot" of cerebral blood flow since scans can be acquired after seizure termination (so long asthe radioactive tracer was injected at the time of the seizure). A significant limitation of SPECT isits poor resolution (about 1 cm) compared to that of MRI.

Like PET, SPECT also can be used to differentiate different kinds of disease processes whichproduce dementia, and it is increasingly used for this purpose. Neuro-PET has a disadvantage ofrequiring use of tracers with half-lives of at most 110 minutes, such as FDG. These must be madein a cyclotron, and are expensive or even unavailable if necessary transport times are prolongedmore than a few half-lives. SPECT, however, is able to make use of tracers with much longer half-lives, such as technetium-99m, and as a result, is far more widely available.



Module 2

CELLULAR BASIS OF BEHAVIOUR

Receptors

Receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of acell, to which one or more specific kinds of signaling molecules may attach. A molecule whichbinds (attaches) to a receptor is called a ligand, and may be a peptide (short protein) or other smallmolecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. Each kind ofreceptor can bind only certain ligand shapes. Each cell typically has many receptors, of manydifferent kinds.

Ligand binding stabilizes a certain receptor conformation (the three-dimensional shape of thereceptor protein, with no change in sequence). This is often associated with gain of or loss ofprotein activity, ordinarily leading to some sort of cellular response. However, some ligands (e.g.antagonists) merely block receptors without inducing any response. Ligand-induced changes inreceptors result in cellular changes which constitute the biological activity of the ligands. Manyfunctions of the human body are regulated by these receptors responding uniquely to specificmolecules like this.

Overview

The shapes and actions of receptors are studied by X-ray crystallography, dual polarisationinterferometry, computer modelling, and structure-function studies, which have advanced theunderstanding of drug action at the binding sites of receptors. Structure activity relationshipscorrelate induced conformational changes with biomolecular activity, and are studied usingdynamic techniques such as circular dichroism and dual polarisation interferometry.

Depending on their functions and ligands, several types of receptors may be identified:

* Some receptor proteins are peripheral membrane proteins.

* Many hormone and neurotransmitter receptors are transmembrane proteins: transmembranereceptors are embedded in the phospholipid bilayer of cell membranes, that allow theactivation of signal transduction pathways in response to the activation by the bindingmolecule, or ligand.

o Metabotropic receptors are coupled to G proteins and affect the cell indirectly through enzymeswhich control ion channels.

o Ionotropic receptors (also known as ligand-gated ion channels) contain a central pore whichopens in response to the binding of ligand.

* Another major class of receptors are intracellular proteins such as those for steroid andintracrine peptide hormone receptors. These receptors often can enter the cell nucleus and modulategene expression in response to the activation by the ligand.

Membrane receptors are isolated from cell membranes by complex extraction procedures usingsolvents, detergents, and/or affinity purification.



Binding and activation

Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from themaccording to the law of mass action.

One measure of how well a molecule fits a receptor is the binding affinity, which is inverselyrelated to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. Thefinal biological response (e.g. second messenger cascade or muscle contraction), is only achievedafter a significant number of receptors are activated.

The receptor-ligand affinity is greater than enzyme-substrate affinity. Whilst both interactions arespecific and reversible, there is no chemical modification of the ligand as seen with the substrateupon binding to its enzyme.

Constitutive activity

A receptor which is capable of producing its biological response in the absence of a bound ligandis said to display "constitutive activity". The constitutive activity of receptors may be blocked byinverse agonist binding. Mutations in receptors that result in increased constitutive activity underliesome inherited diseases, such as precocious puberty (due to mutations in luteinizing hormonereceptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). Forthe use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity.

Agonists versus antagonists

Not every ligand that binds to a receptor also activates the receptor. The following classes ofligands exist:

(Full) agonists are able to activate the receptor and result in a maximal biological response.Most natural ligands are full agonists.

Partial agonists do not activate receptors thoroughly, causing responses which are partialcompared to those of full agonists.

Antagonists bind to receptors but do not activate them. This results in receptor blockage,inhibiting the binding of other agonists.

Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.

Peripheral membrane protein receptors

These receptors are relatively rare compared to the much more common types of receptors thatcross the cell membrane. An example of a receptor that is a peripheral membrane protein is theelastin receptor.

Transmembrane receptors

These receptors are also known as seven transmembrane receptors or 7TM receptors, because theypass through the membrane seven times.



* Muscarinic acetylcholine receptor (Acetylcholine and Muscarine)* Adenosine receptors (Adenosine)* Adrenoceptors (also known as Adrenergic receptors, for adrenaline, and other structurally

related hormones and drugs)* GABA receptors, Type-B (γ-Aminobutyric acid or GABA)* Angiotensin receptors (Angiotensin)* Cannabinoid receptors (Cannabinoids)* Cholecystokinin receptors (Cholecystokinin)* Dopamine receptors (Dopamine)* Glucagon receptors (Glucagon)* Metabotropic glutamate receptors (Glutamate)* Histamine receptors (Histamine)* Olfactory receptors (for the sense of smell)* Opioid receptors (Opioids)* Protease-activated receptors* Rhodopsin (a photoreceptor)* Secretin receptors (Secretin)* Serotonin receptors, except Type-3 (Serotonin, also known as 5-Hydroxytryptamine or 5-HT)* Somatostatin receptors (Somatostatin)* Calcium-sensing receptor (Calcium)* Chemokine receptors (Chemokines)* many more ...

Receptor tyrosine kinases

These receptors detect ligands and propagate signals via the tyrosine kinase of their intracellulardomains. This family of receptors includes;

* Erythropoietin receptor (Erythropoietin)

* Insulin receptor (Insulin)

* Eph receptors

* Insulin-like growth factor 1 receptor

* various other growth factor and cytokine receptors

Guanylyl cyclase receptors

* GC-A & GC-B: receptors for Atrial-natriuretic peptide (ANP) and other natriuretic peptides

* GC-C: Guanylin receptor

Ionotropic receptors

Ionotropic receptors are heteromeric or homomeric oligomers . They are receptors that respond toextracellular ligands and receptors that respond to intracellular ligands.



Role in Genetic Disorders

Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determinewhether the receptor is nonfunctional or the hormone is produced at decreased level; this gives riseto the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreasedhormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.

Receptor Regulation

Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a givenhormone or neurotransmitter to alter its sensitivity to this molecule. This is a locally actingfeedback mechanism.

Effectors and conductor cells

Effector Cells of the Immune System

Monocytes circulate in the blood after leaving the bone marrow. Monocytes usually circulate in theblood for only a day or so before they enter the tissue to mature into macrophages. Monocyteproduction and release from the bone marrow is increased during an immune response. Undernormal conditions, monocytes enter the tissues as resident macrophages in various locations (suchas the skin, lung, liver, spleen, bone marrow and peritoneal cavity). These fixed, residentmacrophages play an important role in keeping the tissues clear of antigen and debris. Moremonocytes are rapidly recruited as needed to these and other sites.

When monocytes enter the tissues and become macrophages they undergo several changes. Thecells enlarge, allowing greater phagocytosis and they increase the amount of digestive enzymes(lysosyme) in their intracellular vesicles (lysosomes) thus facilitating microbe degradation. In thetissues, macrophages live for months and are motile (using pseudopods to move like amoebae).

Macrophages are usually in the resting state unless activated during an immune response.Activation of these cells may happen in response to Th-derived cytokines (especially IFNg) or fromcontact with bacteria or bacterial products. Phagocytosis of pathogens also stimulatesactivation. The activated state is characterized by more efficient phagocytosis and killing ofmicrobes.

There are three major roles that macrophages play in the immune response to pathogens. The firstis their very important role in phagocytosis. In this role they recognize and remove unwantedparticulate matter including products of inflammation and invading organisms, immune complexes,toxins and dying cells. The large number of macrophages in the spleen and liver (where they arecalled Kupffer cells) are particularly important for removal of bacteria from the bloodstream.The second important role macrophages play is as antigen presenting cells (APC) during secondaryimmune responses. Although they are very poor at activating naive T cells they are very good atactivating memory T cells. The great advantage of this is that circulating memory T cells which arerapidly drawn to the site of infection can be immediately activated by macrophages without antigenbeing transported to the local draining node for presentation to T cells. Their third role is cytokinesecretion. After activation, these cells secrete important inflammatory cytokines such as IL-1, IL-6and TNF-a. IL-1 and TNF act to recruit neutrophils and more monocytes from the circulation as



well as having systemic effects (such as fever). In chronic inflammation, macrophages act asscavengers and can become giant cells (via cell fusion) which help form granulomas.

Natural Killer Cells

These cells are sometimes called large granular lymphocytes (LGL's) because they are large,granular and lymphocytes (immunologists are so imaginative!). NK cells have some surfacemarkers in common with T cells, and they are also functionally similar to cytotoxic T lymphocytes(CTL). Like CTL, NK cells are particularly important in the killing of cellular targets (such astumor cells or virus-infected cells). Unlike CTL, however, the killing by NK cells is not antigenspecific, they do not need to recognize specific antigen presented by MHC on the target cell. Infact, it is the very presence or absence of Class I MHC that appears to be involved in NK cellactivation. It is thought that many tumor cells are too busy proliferating to bother about expressingthe normal surface molecules at normal levels. The lack of normal levels of Class I MHC on theurface of tumor cells is sufficient to activate NK cells to kill them.

NK cells do not have a T cell receptor and are not T cells but they kill target cells in the samemanner as CTL kill targets (see above). However, they also produce large amounts of tumornecrosis factor alpha (TNF-a). This factor has many functions but one important one in thiscontext is that it binds to the TNF receptor on target cells and induces apoptosis.

Recent data have shown that NK cells also produce a lot of IFN-g, which is very interesting sincethis cytokine activates macrophages and stimulates them to produce large amounts of TNF-a.

Neutrophils

Neutrophils are produced in the bone marrow from the granulocyte-monocyte stem cell. These cellsare often called polymorphonuclear cells (PMN's). This is because of the polymorphic shape of thenucleus. Sometimes the terms neutrophil and PMN are used interchangeably. Neutrophils are themost common white blood cells in the circulation, making up about 60-70% of the total WBCcount. They are very short-lived cells, circulating in the blood for about 8 hours after their releasefrom the bone marrow. If induced to migrate out of the blood into the tissues, they will engage in avariety of effector functions before dying by apoptosis within 1-2 days.

Neutrophils are attracted into the tissue by chemotactic factors that include Complement proteins,clotting proteins, cytokines and chemokines. They are the first cells to arrive at the site ofinflammation by leaving the blood, through the endothelium into the tissue (called “transmigration”or “emigration”). The appearance of neutrophils in the tissue is associated with bacterial infection,acute tissue injury, immune complex-Complement activation, necrosis and tissue remodeling. Inthe tissues, neutrophils are very active phagocytic cells. They are the most effective at killingingested microorganisms and can do this by oxygen dependent pathways (such as superoxide anion[O2-] and hydrogen peroxide [H2O2]), nitrogen dependent pathways (nitric oxide [NO]) orindependent pathways (such as defensins and digestive enzymes). Neutrophils, however, do notnormally act as antigen presenting cells.



Eosinophils

Eosinophils are named because of their intense staining with 'eosin'. Under the microscope,eosinophils typically have a bi-lobed nucleus and contain many basic crystal granules in theircytoplasm. The granules are eosinophil mediators that are toxic to many organisms and also totissues. Eosinophils circulate in the blood and emigrate into tissues, are phagocytic, and have beenlinked with anti-parasite immunity. Recently, eosinophils have been suggested to play a major rolein the lung pathology associated with the late phase of asthma. There is also some evidence thatthey may be involved in immune responses against breast and colon tumors.

Mast Cells

Mast cells are formed in the tissue from undifferentiated precursor cells released into the bloodfrom the bone marrow. They are not the tissue counterparts of basophils but they are similar inmany respects. Mast cells contain numerous granules with preformed mediators which can bereleased from mast cells after stimulation. The preformed mediators include histamine and otheractive substances, including some cytokines (such TNF-a).

Stimulation of mast cells also results in the production of newly formed mediators such asprostaglandins and leukotrienes. Stimulation of mast cells occurs in several ways such as by theanaphylatoxins (C3a and C5a) of the Complement system or by the cross-linking of surfaceIgE. Mast cells have high affinity Fc receptors for the IgE that is produced against an allergen. Asa result, mast cell release is most significant in either acute inflammation or in allergic responses.

Basophils

Basophils are found in low numbers in the blood. Their functions are not well understood but theyare known to be involved in Type I hypersensitivity (allergic) responses. These cells have highaffinity Fc receptors for IgE on their surface. Cross-linking of the IgE causes the basophils torelease pharmacologically active mediators such as heparin and histamine. Basophils, therefore, actvery much like mast cells except that they are in the blood instead of the tissues.

CD4+ Lymphocyte plays a central role in the immune system, which has been linked to that of theconductor of an orchestra.

A Typical Cell – Structures and Function

The cell is the functional basic unit of life. It was discovered by Robert Hooke and is the functionalunit of all known living organisms. It is the smallest unit of life that is classified as a living thing,and is often called the building block of life. Some organisms, such as most bacteria, are unicellular(consist of a single cell). Other organisms, such as humans, are multicellular. (Humans have about100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 nanogram. The largestcells are about 135 µm in the anterior horn in the spinal cord while granule cells in the cerebellum,the smallest, can be some 4 µm and the longest cell can reach from the toe to the lower brain stem(Pseudounipolar cells).) The largest known cells are unfertilised ostrich egg cells which weigh 3.3pounds.



In 1835, before the final cell theory was developed, Jan Evangelista Purkyně observed small"granules" while looking at the plant tissue through a microscope. The cell theory, first developedin 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composedof one or more cells, that all cells come from preexisting cells, that vital functions of an organismoccur within cells, and that all cells contain the hereditary information necessary for regulating cellunctions and for transmitting information to the next generation of cells.

The word cell comes from the Latin cellula, meaning, a small room. The descriptive term for thesmallest living biological structure was coined by Robert Hooke in a book he published in 1665when he compared the cork cells he saw through his microscope to the small rooms monks lived in.

Anatomy of cells

There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually independent,while eukaryotic cells are often found in multicellular organisms.

Prokaryotic cells

The prokaryote cell is simpler, and therefore smaller, than a eukaryote cell, lacking a nucleus andmost of the other organelles of eukaryotes. There are two kinds of prokaryotes: bacteria and archaea;these share a similar structure.

A prokaryotic cell has three architectural regions:

* On the outside, flagella and pili project from the cell's surface. These are structures (not presentin all prokaryotes) made of proteins that facilitate movement and communication between cells;

* Enclosing the cell is the cell envelope – generally consisting of a cell wall covering a plasmamembrane though some bacteria also have a further covering layer called a capsule. The envelopegives rigidity to the cell and separates the interior of the cell from its environment, serving as aprotective filter. Though most prokaryotes have a cell wall, there are exceptions such asMycoplasma (bacteria) and Thermoplasma (archaea). The cell wall consists of peptidoglycan inbacteria, and acts as an additional barrier against exterior forces. It also prevents the cell fromexpanding and finally bursting (cytolysis) from osmotic pressure against a hypotonic environment.Some eukaryote cells (plant cells and fungi cells) also have a cell wall;

* Inside the cell is the cytoplasmic region that contains the cell genome (DNA) and ribosomes andvarious sorts of inclusions. A prokaryotic chromosome is usually a circular molecule (an exceptionis that of the bacterium Borrelia burgdorferi, which causes Lyme disease). Though not forming anucleus, the DNA is condensed in a nucleoid. Prokaryotes can carry extrachromosomal DNAelements called plasmids, which are usually circular. Plasmids enable additional functions, such asantibiotic resistance.

Eukaryotic cells

Organelles:

(1) nucleolus

(2) nucleus

(3) ribosome



(4) vesicle

(5) rough endoplasmic reticulum (ER)

(6) Golgi apparatus

(7) Cytoskeleton

(8) smooth endoplasmic reticulum

(9) mitochondria

(10) vacuole

(11) cytoplasm

(12) lysosome

(13) centrioles within centrosome

Eukaryotic cells are about 15 times wider than a typical prokaryote and can be as much as 1000times greater in volume. The major difference between prokaryotes and eukaryotes is that eukaryoticcells contain membrane-bound compartments in which specific metabolic activities take place. Mostimportant among these is a cell nucleus, a membrane-delineated compartment that houses theeukaryotic cell's DNA. This nucleus gives the eukaryote its name, which means "true nucleus."Other differences include:

* The plasma membrane resembles that of prokaryotes in function, with minor differences in thesetup. Cell walls may or may not be present.

* The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, whichare associated with histone proteins. All chromosomal DNA is stored in the cell nucleus, separatedfrom the cytoplasm by a membrane. Some eukaryotic organelles such as mitochondria also containsome DNA.

* Many eukaryotic cells are ciliated with primary cilia. Primary cilia play important roles inchemosensation, mechanosensation, and thermosensation. Cilia may thus be "viewed as sensorycellular antennae that coordinate a large number of cellular signaling pathways, sometimes couplingthe signaling to ciliary motility or alternatively to cell division and differentiation."

* Eukaryotes can move using motile cilia or flagella. The flagella are more complex than those ofprokaryotes.

Subcellular components

All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates itsinterior from its environment, regulates what moves in and out (selectively permeable), andmaintains the electric potential of the cell. Inside the membrane, a salty cytoplasm takes up most ofthe cell volume. All cells possess DNA, the hereditary material of genes, and RNA, containing theinformation necessary to build various proteins such as enzymes, the cell's primary machinery. Thereare also other kinds of biomolecules in cells. This article will list these primary components of thecell, then briefly describe their function.



Cell membrane: A cell's defining boundary

The cytoplasm of a cell is surrounded by a cell membrane or plasma membrane. The plasmamembrane in plants and prokaryotes is usually covered by a cell wall. This membrane serves toseparate and protect a cell from its surrounding environment and is made mostly from a double layerof lipids (hydrophobic fat-like molecules) and hydrophilic phosphorus molecules. Hence, the layer iscalled a phospholipid bilayer. It may also be called a fluid mosaic membrane. Embedded within thismembrane is a variety of protein molecules that act as channels and pumps that move differentmolecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can eitherlet a substance (molecule or ion) pass through freely, pass through to a limited extent or not passthrough at all. Cell surface membranes also contain receptor proteins that allow cells to detectexternal signaling molecules such as hormones.

Cytoskeleton: A cell's scaffold

The cytoskeleton acts to organize and maintain the cell's shape; anchors organelles in place; helpsduring endocytosis, the uptake of external materials by a cell, and cytokinesis, the separation ofdaughter cells after cell division; and moves parts of the cell in processes of growth and mobility.The eukaryotic cytoskeleton is composed of microfilaments, intermediate filaments andmicrotubules. There is a great number of proteins associated with them, each controlling a cell'sstructure by directing, bundling, and aligning filaments. The prokaryotic cytoskeleton is less well-studied but is involved in the maintenance of cell shape, polarity and cytokinesis.

Genetic material

Two different kinds of genetic material exist: deoxyribonucleic acid (DNA) and ribonucleic acid(RNA). Most organisms use DNA for their long-term information storage, but some viruses (e.g.,retroviruses) have RNA as their genetic material. The biological information contained in anorganism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g.,mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the geneticcode itself. Transfer RNA (tRNA) molecules are used to add amino acids during protein translation.

Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterialchromosome) in the nucleoid region of the cytoplasm. Eukaryotic genetic material is divided intodifferent, linear molecules called chromosomes inside a discrete nucleus, usually with additionalgenetic material in some organelles like mitochondria and chloroplasts (see endosymbiotic theory).

A human cell has genetic material contained in the cell nucleus (the nuclear genome) and in themitochondria (the mitochondrial genome). In humans the nuclear genome is divided into 23 pairs oflinear DNA molecules called chromosomes. The mitochondrial genome is a circular DNA moleculedistinct from the nuclear DNA. Although the mitochondrial DNA is very small compared to nuclearchromosomes, it codes for 13 proteins involved in mitochondrial energy production and specifictRNAs.

Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by aprocess called transfection. This can be transient, if the DNA is not inserted into the cell's genome,or stable, if it is. Certain viruses also insert their genetic material into the genome.



Organelles

The human body contains many different organs, such as the heart, lung, and kidney, with eachorgan performing a different function. Cells also have a set of "little organs," called organelles, thatare adapted and/or specialized for carrying out one or more vital functions.

There are several types of organelles within an animal cell. Some (such as the nucleus and golgiapparatus) are typically solitary, while others (such as mitochondria, peroxisomes and lysosomes)can be numerous (hundreds to thousands). The cytosol is the gelatinous fluid that fills the cell andsurrounds the organelles.

Cell nucleus – a cell's information center

The cell nucleus is the most conspicuous organelle found in a eukaryotic cell. It houses the cell'schromosomes, and is the place where almost all DNA replication and RNA synthesis (transcription)occur. The nucleus is spherical and separated from the cytoplasm by a double membrane called thenuclear envelope. The nuclear envelope isolates and protects a cell's DNA from various moleculesthat could accidentally damage its structure or interfere with its processing. During processing, DNAis transcribed, or copied into a special RNA, called messenger RNA (mRNA). This mRNA is thentransported out of the nucleus, where it is translated into a specific protein molecule. The nucleolusis a specialized region within the nucleus where ribosome subunits are assembled. In prokaryotes,DNA processing takes place in the cytoplasm.

Mitochondria and Chloroplasts – the power generators

Mitochondria are self-replicating organelles that occur in various numbers, shapes, and sizes inthe cytoplasm of all eukaryotic cells. Mitochondria play a critical role in generating energy in theeukaryotic cell. Mitochondria generate the cell's energy by oxidative phosphorylation, using oxygento release energy stored in cellular nutrients (typically pertaining to glucose) to generate ATP.Mitochondria multiply by splitting in two. Respiration occurs in the cell mitochondria.

Organelles that are modified chloroplasts are broadly called plastids, and are involved in energystorage through photosynthesis, which uses solar energy to generate carbohydrates and oxygen fromcarbon dioxide and water.

Mitochondria and chloroplasts each contain their own genome, which is separate and distinct fromthe nuclear genome of a cell. Both organelles contain this DNA in circular plasmids, much likeprokaryotic cells, strongly supporting the evolutionary theory of endosymbiosis; since theseorganelles contain their own genomes and have other similarities to prokaryotes, they are thought tohave developed through a symbiotic relationship after being engulfed by a primitive cell.

Endoplasmic reticulum – eukaryotes only

The endoplasmic reticulum (ER) is the transport network for molecules targeted for certainmodifications and specific destinations, as compared to molecules that will float freely in thecytoplasm. The ER has two forms: the rough ER, which has ribosomes on its surface and secretesproteins into the cytoplasm, and the smooth ER, which lacks them. Smooth ER plays a role incalcium sequestration and release.



Golgi apparatus – eukaryotes only

The primary function of the Golgi apparatus is to process and package the macromolecules suchas proteins and lipids that are synthesized by the cell. It is particularly important in the processing ofproteins for secretion. The Golgi apparatus forms a part of the endomembrane system of eukaryoticcells. Vesicles that enter the Golgi apparatus are processed in a cis to trans direction, meaning theycoalesce on the cis side of the apparatus and after processing pinch off on the opposite (trans) side toform a new vesicle in the animal cell.

Ribosomes

The ribosome is a large complex of RNA and protein molecules. They each consist of two subunits,and act as an assembly line where RNA from the nucleus is used to synthesise proteins from aminoacids. Ribosomes can be found either floating freely or bound to a membrane (the roughendoplasmatic reticulum in eukaryotes, or the cell membrane in prokaryotes).

Lysosomes and Peroxisomes – eukaryotes only

Lysosomes contain digestive enzymes (acid hydrolases). They digest excess or worn-outorganelles, food particles, and engulfed viruses or bacteria. Peroxisomes have enzymes that rid thecell of toxic peroxides. The cell could not house these destructive enzymes if they were notcontained in a membrane-bound system. These organelles are often called a "suicide bag" becauseof their ability to detonate and destroy the cell.

Centrosome – the cytoskeleton organizer

The centrosome produces the microtubules of a cell – a key component of the cytoskeleton. Itdirects the transport through the ER and the Golgi apparatus. Centrosomes are composed of twocentrioles, which separate during cell division and help in the formation of the mitotic spindle. Asingle centrosome is present in the animal cells. They are also found in some fungi and algae cells.

Vacuoles

Vacuoles store food and waste. Some vacuoles store extra water. They are often described asliquid filled space and are surrounded by a membrane. Some cells, most notably Amoeba, havecontractile vacuoles, which can pump water out of the cell if there is too much water.Thevacuolesofeukaryotic cells are usually larger in those of plants than animals.

Structures outside the cell wall

Capsule

A gelatinous capsule is present in some bacteria outside the cell wall. The capsule may bepolysaccharide as in pneumococci, meningococci or polypeptide as Bacillus anthracis or hyaluronicacid as in streptococci.[citation needed] Capsules are not marked by ordinary stain and can bedetected by special stain. The capsule is antigenic. The capsule has antiphagocytic function so itdetermines the virulence of many bacteria. It also plays a role in attachment of the organism tomucous membranes.



Flagella

Flagella are the organelles of cellular mobility. They arise from cytoplasm and extrude through thecell wall. They are long and thick thread-like appendages, protein in nature. Are most commonlyfound in bacteria cells but are found in animal cells as well.

Fimbriae (pili)

They are short and thin hair like filaments, formed of protein called pilin (antigenic). Fimbriae areresponsible for attachment of bacteria to specific receptors of human cell (adherence). There arespecial types of pili called (sex pili) involved in conjunction.

Cell functions

Cell growth and metabolism

Between successive cell divisions, cells grow through the functioning of cellular metabolism. Cellmetabolism is the process by which individual cells process nutrient molecules. Metabolism hastwo distinct divisions: catabolism, in which the cell breaks down complex molecules to produceenergy and reducing power, and anabolism, in which the cell uses energy and reducing power toconstruct complex molecules and perform other biological functions. Complex sugars consumed bythe organism can be broken down into a less chemically complex sugar molecule called glucose.Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form ofenergy, through two different pathways.

The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Eachreaction is designed to produce some hydrogen ions that can then be used to make energy packets(ATP). In prokaryotes, glycolysis is the only method used for converting energy.

The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria andcan generate enough ATP to run all the cell functions.

Creation of new cells

Cell division involves a single cell (called a mother cell) dividing into two daughter cells. Thisleads to growth in multicellular organisms (the growth of tissue) and to procreation (vegetativereproduction) in unicellular organisms.

Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of nucleardivision, called mitosis, followed by division of the cell, called cytokinesis. A diploid cell may alsoundergo meiosis to produce haploid cells, usually four. Haploid cells serve as gametes inmulticellular organisms, fusing to form new diploid cells.

DNA replication, or the process of duplicating a cell's genome, is required every time a cell divides.Replication, like all cellular activities, requires specialized proteins for carrying out the job.



Protein synthesis

Cells are capable of synthesizing new proteins, which are essential for the modulation andmaintenance of cellular activities. This process involves the formation of new protein moleculesfrom amino acid building blocks based on information encoded in DNA/RNA. Protein synthesisgenerally consists of two major steps: transcription and translation.

Transcription is the process where genetic information in DNA is used to produce a complementaryRNA strand. This RNA strand is then processed to give messenger RNA (mRNA), which is free tomigrate through the cell. mRNA molecules bind to protein-RNA complexes called ribosomeslocated in the cytosol, where they are translated into polypeptide sequences. The ribosome mediatesthe formation of a polypeptide sequence based on the mRNA sequence. The mRNA sequencedirectly relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter moleculesin binding pockets within the ribosome. The new polypeptide then folds into a functional three-dimensional protein molecule.

Cell movement or motility

Cells can move during many processes: such as wound healing, the immune response and cancermetastasis. For wound healing to occur, white blood cells and cells that ingest bacteria move to thewound site to kill the microorganisms that cause infection.

At the same time fibroblasts (connective tissue cells) move there to remodel damaged structures. Inthe case of tumor development, cells from a primary tumor move away and spread to other parts ofthe body. Cell motility involves many receptors, crosslinking, bundling, binding, adhesion, motorand other proteins.

The process is divided into three steps – protrusion of the leading edge of the cell, adhesion of theleading edge and de-adhesion at the cell body and rear, and cytoskeletal contraction to pull the cellforward. Each step is driven by physical forces generated by unique segments of the cytoskeleton.

Evolution

The origin of cells has to do with the origin of life, which began the history of life on Earth.

Origin of the first cell

There are several theories about the origin of small molecules that could lead to life in an earlyEarth. One is that they came from meteorites (see Murchison meteorite). Another is that they werecreated at deep-sea vents. A third is that they were synthesized by lightning in a reducingatmosphere (see Miller–Urey experiment); although it is not clear if Earth had such an atmosphere.There are essentially no experimental data defining what the first self-replicating forms were. RNAis generally assumed to be the earliest self-replicating molecule, as it is capable of both storinggenetic information and catalyzing chemical reactions (see RNA world hypothesis). But some otherentity with the potential to self-replicate could have preceded RNA, like clay or peptide nucleicacid.

Cells emerged at least 4.0–4.3 billion years ago. The current belief is that these cells wereheterotrophs. An important characteristic of cells is the cell membrane, composed of a bilayer oflipids. The early cell membranes were probably more simple and permeable than modern ones,



with only a single fatty acid chain per lipid. Lipids are known to spontaneously form bilayeredvesicles in water, and could have preceded RNA. But the first cell membranes could also have beenproduced by catalytic RNA, or even have required structural proteins before they could form.

Origin of eukaryotic cells

The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearing organelles like the mitochondria and the chloroplasts are almost certainly what remains ofancient symbiotic oxygen-breathing proteobacteria and cyanobacteria, respectively, where the restof the cell seems to be derived from an ancestral archaean prokaryote cell – a theory termed theendosymbiotic theory.

There is still considerable debate about whether organelles like the hydrogenosome predated theorigin of mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extanteukaryotes, may have played a role in the transition from prokaryotes to eukaryotes. An 'origin ofsex as vaccination' theory suggests that the eukaryote genome accreted from prokaryan parasitegenomes in numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose wheninfected hosts began swapping nuclearized genomes containing co-evolved, vertically transmittedsymbionts that conveyed protection against horizontal infection by more virulent symbionts.

STRUCTURE AND FUNCTION OF DIFFERENT TISSUES

Epithelial Tissue

Epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughoutthe body. Many glands are also formed from epithelial tissue. It lies on top of connective tissue, andthe two layers are separated by a basement membrane.

In humans, epithelium is classified as a primary body tissue, the other ones being connective tissue,muscle tissue and nervous tissue.

Epithelium is often defined by the expression of the adhesion molecule e-cadherin (as opposed to n-cadherin, which is used by cells of the connective tissue).

Functions of epithelial cells include secretion, selective absorption, protection, transcellulartransport and detection of sensation. As a result, they commonly present extensive apical-basolateral polarity (e.g. different membrane proteins expressed) and specialization.

General characters of epithelial tissue

It may develop from ectoderm , mesoderm ,or endoderm.

The epithelial cells rest on a basement membrane which may be clear or not clear.

No blood vessels can enter in between epithelial cells but nerves can , so epithelial tissue isavascular tissue.

Epithelial tissue receives nutrition by diffusion from the underlying connective tissue.



Classification (structural)

Epithelial tissue can be structurally divided into two groups depending on the number of layers ofwhich it is composed. Epithelial tissue that is only one cell thick is known as simple epithelium. Ifit is two or more cells thick, it is known as stratified epithelium.

However, when taller simple epithelial cells (see columnar, below) are viewed in cross section withseveral nuclei appearing at different heights, they can be confused with stratified epithelia. Thiskind of epithelium is therefore described as "pseudostratified" epithelium.

Regardless of the type, any epithelium is separated from the underlying tissue by a thin layer ofconnective tissue known as the basement membrane. The basement membrane provides structuralsupport for the epithelium and also binds it to neighbouring structures.

Simple epithelium

Simple epithelium is one cell thick; that is, every cell is in contact with the underlying basementmembrane. Simple epithelium can be subdivided further according to the shape and function of itscells.

Stratified Epithelium

Stratified epithelium differs from simple epithelium in that it is multilayered. It is therefore foundwhere body linings have to withstand mechanical or chemical insult such that layers can be abradedand lost without exposing subepithelial layers. Cells flatten as the layers become more apical,though in their most basal layers the cells can be squamous, cuboidal or columnar.

Functions

* Protection: Epithelial cells protect underlying tissue from mechanical injury, harmfulchemicals and pathogens and excessive water loss.

* Sensation: Sensory stimuli are detected by specialized epithelial cells. Specialized epithelialtissue containing sensory nerve endings is found in the skin, eyes, ears and nose and on the tongue.

* Secretion: In glands, epithelial tissue is specialized to secrete specific chemical substancessuch as enzymes, hormones and lubricating fluids.

* Absorption: Certain epithelial cells lining the small intestine absorb nutrients from thedigestion of food.

* Excretion: Epithelial tissues in the kidney excrete waste products from the body and reabsorbneeded materials from the urine. Sweat is also excreted from the body by epithelial cells in thesweat glands.

* Diffusion: Simple epithelium promotes the diffusion of gases, liquids and nutrients. Becausethey form such a thin lining, they are ideal for the diffusion of gases (e.g. walls of capillaries andlungs).



Location

Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermostlayer of our skin is composed of dead stratified squamous, keratinized epithelial cells.

Tissues that line the inside of the mouth, the oesophagus and part of the rectum are composed ofnonkeratinized stratified squamous epithelium. Other surfaces that separate body cavities from theoutside environment are lined by simple squamous, columnar, or pseudostratified epithelial cells.Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive andurinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea iscovered with fast-growing, easily-regenerated epithelial cells. Endothelium (the inner lining ofblood vessels, the heart, and lymphatic vessels) is a specialized form of epithelium. Another type,mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.

Cell junctions

A cell junction is a structure within a tissue of a multicellular organism. Cell junctions areespecially abundant in epithelial tissues. They consist of protein complexes and provide contactbetween neighbouring cells, between a cell and the extracellular matrix, or they built up theparacellular barrier of epithelia and control the paracellular transport.

Secretory epithelia

As stated above, secretion is one major function of epithelial cells. Glands are formed from theinvagination / infolding of epithelial cells and subsequent growth in the underlying connectivetissue. There are two major classifications of glands: endocrine glands and exocrine glands.Endocrine glands are glands that secrete their product directly onto a surface rather than through aduct. This group contains the glands of the Endocrine system.

Sensing the extracellular environment

"Some epithelial cells are ciliated, and they commonly exist as a sheet of polarised cells forming atube or tubule with cilia projecting into the lumen." Primary cilia on epithelial cells providechemosensation, thermosensation and mechanosensation of the extracellular environment byplaying "a sensory role mediating specific signalling cues, including soluble factors in the externalcell environment, a secretory role in which a soluble protein is released to have an effectdownstream of the fluid flow, and mediation of fluid flow if the cilia are motile."

Embryology

In general, there are epithelial tissues deriving from all of the embryological germ layers:

* from ectoderm (e.g., the epidermis);

* from endoderm (e.g., the lining of the gastrointestinal tract);

* from mesoderm (e.g., the inner linings of body cavities).

However, it is important to note that pathologists do not consider endothelium and mesothelium(both derived from mesoderm) to be true epithelium. This is because such tissues present very



different pathology. For that reason, pathologists label cancers in endothelium and mesotheliumsarcomas, whereas true epithelial cancers are called carcinomas. Also, the filaments that supportthese mesoderm-derived tissues are very distinct. Outside of the field of pathology, it is, in general,accepted that the epithelium arises from all three germ layers.

Connective tissue

Connective tissue is a form of fibrous tissue.. It is one of the four types of tissue in traditionalclassifications (the others being epithelial, muscle, and nervous tissue).

Collagen is the main protein of connective tissue in animals and the most abundant protein inmammals, making up about 25% of the total protein content.

Fiber types

Fiber types as follows:

* collagenous fibers

* elastic fibers

* Bone Marrow

Disorders of connective tissue

Various connective tissue conditions have been identified; these can be both inherited andenvironmental.

* Marfan syndrome - a genetic disease causing abnormal fibrillin.

* Scurvy - caused by a dietary deficiency in vitamin C, leading to abnormal collagen.

* Ehlers-Danlos syndrome - deficient type III collagen- a genetic disease causing progressivedeterioration of collagens, with different EDS types affecting different sites in the body, such asjoints, heart valves, organ walls, arterial walls, etc.

* Loeys-Dietz syndrome - a genetic disease related to Marfan syndrome, with an emphasis onvascular deterioration.

* Pseudoxanthoma elasticum - an autosomal recessive hereditary disease, caused by calcificationand fragmentation of elastic fibres, affecting the skin, the eyes and the cardiovascular system.

* Systemic lupus erythematosus - a chronic, multisystem, inflammatory disorder of probableautoimmune etiology, occurring predominantly in young women.

* Osteogenesis imperfecta (brittle bone disease) - caused by insufficient production of good qualitycollagen to produce healthy, strong bones.

* Fibrodysplasia ossificans progressiva - disease of the connective tissue, caused by a defectivegene which turns connective tissue into bone.



* Spontaneous pneumothorax - collapsed lung, believed to be related to subtle abnormalities inconnective tissue.

* Sarcoma - a neoplastic process originating within connective tissue.

Staining of connective tissue

For microscopic viewing, the majority of the connective tissue staining techniques color tissuefibers in contrasting shades. Collagen may be differentially stained by any of the followingtechniques:

Van Gieson's stain

Masson's Trichrome stain

Mallory's Aniline Blue stain

Azocarmine stain

Krajian's Aniline Blue stain

Muscular Tissue

Muscular tissue is the basic tissue characterized by the ability to contract upon stimulation.Muscular tissues are vascularized tissues chiefly composed of elongated cells that are excitable andcontractile, and usually arranged in parallel. In the body, there are three types of muscular tissue:skeletal muscle, smooth muscle, and cardiac muscle.

Description

Muscular tissue is largely composed of muscle cells. Muscle cells are elongated and surrounded byexternal lamina, which is similar to basal lamina of epithelial tissues. Muscle cells contain acontractile apparatus composed of actin (thin) and myosin (thick) filaments, and associatedproteins. In striated muscle cells, the contractile apparatus is organized into myofibrils, which areoriented in the same direction as the long axis of the muscle cell. The regular repeating segments(sacromeres) of myofibrils give skeletal and cardiac muscle cells transverse striations. In smoothmuscle cells, the contractile apparatus, actin and myosin filaments form contractile fibers, which donot appear as highly organized as myofibrils.

Skeletal Muscle

Skeletal muscle cells, also known as skeletal muscle fibers, are very long, multinucleated syncytialcells that were formed during development by fusion of myoblast cells. Relative to other musclecells, skeletal muscle cells are long and wide.

In cross section, skeletal muscle cells are polygonal in shape, and their nuclei are locatedperipherally, adjacent to the plasma membrane (sarcolemma).



Cardiac Muscle

Cardiac muscle fibers are composed of branching and anastomosing chains of cardiac muscle cells.Cardiac muscle cells within a fiber are joined to their neighbors by intercalated discs, which containanchoring and gap junctions. The anchoring junctions (adherens junctions and desmosomes)physically connect the cytoskeletons and contractile apparatuses of the neighboring cells. The gapjunctions electrically couple the cells.

In cross section, cardiac muscle cells are rounded in shape, have a single central nucleus, and areintermediate in size between skeletal and smooth muscle cells.

Smooth Muscle

Smooth muscle is composed of sheets or bundles of relatively short, spindle-shaped cells, in astaggered array. Smooth muscle cells are not striated, and have a single central nucleus. In somesmooth muscle, the cells are interconnected by gap junctions.

In cross section, smooth muscle cells are circular. Diameters of cross-sectional profiles differ; thelargest profiles display a central nucleus.

Role of Muscular Tissue in the Body

The special role of muscular tissues is contraction, an ability the body puts to multiple uses.

Skeletal muscle makes up the muscles of the muscular system. As part of themusculoskeletal system, skeletal muscle is involved in body posture and movement.Skeletal muscle is also found in the extra-ocular muscles, and muscles of the auditoryossicles, tongue, soft palate and fauces, pharynx, larynx, pelvic diaphragm, and perineum.

Smooth muscle in the walls of hollow visceral organs, ducts, arteries, and veins controls themovement of contents in the lumen. Some bundles of smooth muscle form sphincters.Smooth muscle is also found in arrector pili muscles of the skin, and in intrinsic muscles ofthe eye.

Cardiac muscle in the walls of the atria and ventricles of the heart pump blood through thecardiovascular system

Working

Muscle tissue contracts following excitation. Excitation of muscle cells causes an increase incalcium ion concentration in the cytosol. Calcium ions bind to proteins that regulate the interactionof actin and myosin filaments, triggering contraction. Muscle tissue types differ in the details of theexcitation and initiation of actin-myosin interactions.

Skeletal muscle

Muscles of the skeletal system are generally considered voluntary muscles, because they can besubject to conscious control. Muscle contraction may also be subconscious, such as reflexmovements. Muscles are innervated by cranial or spinal nerves.



Skeletal muscle fibers form neuromuscular junctions with motor neurons, whose cell bodies arelocated in the spinal cord or brainstem. A motor unit consists of a motor neuron and the fibers thatit innervates.

Neurotransmission at the neuromuscular junction causes depolarization of the sarcolemma andtransverse tubules. Depolarization releases calcium ions from the sacroplasmic reticulum into thecytosol, where it binds troponin C, allowing interaction of actin and myosin filaments.

Cardiac muscle

The contraction of cardiac muscle is involuntary, strong, and rhythmical. Cardiac muscle cells havean intrinsic pacemaker mechanism. Cardiac muscle cells with the highest pacemaker rate determinethe rate of contraction of all cardiac muscle fibers to which they are connected. The rate and forceof contraction can also be modified by hormones and the autonomic nervous system.

Cardiac muscle cells are excited by depolarization through the fiber spread by gap junctions.Depolarization leads to increased calcium in the cytosol from the extracellular space, as well assarcoplasmic reticulum. Actin-myosin interactions are triggered by binding of calcium by troponinC, as in skeletal muscle.

Smooth muscle

Smooth muscle contraction is involuntary. Physiologically, smooth muscle is often described asbeing either multi-unit or unitary. In multi-unit smooth muscle, such as the muscles in the iris, thecells are not interconnected by gap junctions. These cells are individually controlled by theautonomic nervous system.

In unitary smooth muscle, the cells are interconnected by gap junctions. Contraction of unitarysmooth muscle, for example, in the walls of the intestines, is often described as slow and rhythmic.The rate and force of contraction are modulated by the autonomic nervous system and hormones.

Excitation of smooth muscle cells, either by autonomic nerve fibers or through gap junctions,causes extracellular calcium ions to enter the cytosol. Calmodulin binds calcium ions and activatesmyosin light-chain kinase, which phosphorylates a myosin light chain, unmasking myosin's actin-binding site.

Nervous tissue

Nervous tissue is one of four major classes of vertebrate tissue.

Nervous tissue is the main component of the nervous system-the brain, spinal cord, and nerves-which regulates and controls body functions. It is composed of neurons, which transmit impulses,and the neuroglialcells, which assist propagation of the nerve impulse as well as provide nutrientsto the neuron.

Nervous tissue is made of nerve cells that come in many varieties, all of which are distinctlycharacteristic by the axon or long stem like part of the cell that sends action potential signals to thenext cell.



Functions of the nervous system are sensory input, integration, controls of muscles and glands,homeostasis, and mental activity.

All living cells have the ability to react to stimuli. Nervous tissue is specialized to react to stimuliand to conduct impulses to various organs in the body which bring about a response to the stimulus.Nerve tissue (as in the brain, spinal cord and peripheral nerves that branch throughout the body) areall made up of specialized nerve cells called neurons. Neurons are easily stimulated and transmitimpulses very rapidly. A nerve is made up of many nerve cell fibers (neurons) bound together byconnective tissue. A sheath of dense connective tissue, the epineurium surrounds the nerve. Thissheath penetrates the nerve to form the perineurium which surrounds bundles of nerve fibers. Bloodvessels of various sizes can be seen in the epineurium. The endoneurium, which consists of a thinlayer of loose connective tissue, surrounds the individual nerve fibers.

The cell body is enclosed by a cell (plasma) membrane and has a central nucleus. Granules calledNissl bodies are found in the cytoplasm of the cell body. Within the cell body, extremely fineneurofibrils extend from the dendrites into the axon. The axon is surrounded by the myelin sheath,which forms a whitish, non-cellular, fatty layer around the axon. Outside the myelin sheath is acellular layer called the neurilemma or sheath of Schwann cells. The myelin sheath together withthe neurilemma is also known as the medullary sheath. This medullary sheath is interrupted atintervals by the nodes of Ranvier.

Neuronal Communication

Nerve cells are functionally made to each other at a junction known as a synapse, where theterminal branches of an axon and the dendrites of another neuron lie in close proximity to eachother but normally without direct contact. Information is transmitted across the gap by chemicalsecretions called neurotransmitters. It causes activation in the post-synaptic cell.All cells possessthe ability to respond to stimuli. The messages carried by the nervous system are electrical signalscalled impulses.

Classification of Neurons

Neurons are classified both structurally and functionally.

Structural Classification Neurons are grouped structurally according to the number of processesextending from their cell body. Three major neuron groups make up this classification: multipolar(polar = end, pole), bipolar and unipolar neurons.

Multipolar Neurons (3+ processes)

They are the most common neuron type in humans (more than 99% of neurons belong to thisclass) and the major neuron type in the CNS

Bipolar Neurons

Bipolar neurons are spindle-shaped, with a dendrite at one end and an axon at the other . Anexample can be found in the light-sensitive retina of the eye.



Unipolar Neurons

Sensory neurons have only a single process or fibre which divides close to the cell body into twomain branches (axon and dendrite). Because of their structure they are often referred to as unipolarneurons.

Cancer

Tumors in nervous tissue include:

* Gliomas (glial cell tumors)

Gliomatosis cerebri, Oligoastrocytoma, Choroid plexus papilloma, Ependymoma, Astrocytoma(Pilocytic astrocytoma, Glioblastoma multiforme), Dysembryoplastic neuroepithelial tumour,Oligodendroglioma, Medulloblastoma, Primitive neuroectodermal tumor

* Neuroepitheliomatous tumors

Ganglioneuroma, Neuroblastoma, Atypical teratoid rhabdoid tumor, Retinoblastoma,Esthesioneuroblastoma

* Nerve sheath tumors

Neurofibroma (Neurofibrosarcoma, Neurofibromatosis), Schwannoma, Neurinoma, Acousticneuroma, Neuroma

Genes – Structure and Function, How do genes work?

A gene is a unit of heredity in a living organism. It is normally a stretch of DNA that codes for atype of protein or for an RNA chain that has a function in the organism. All proteins and functionalRNA chains are specified by genes. All living things depend on genes. Genes hold the informationto build and maintain an organism's cells and pass genetic traits to offspring. A modern workingdefinition of a gene is "a locatable region of genomic sequence, corresponding to a unit ofinheritance, which is associated with regulatory regions, transcribed regions, and or other functionalsequence regions ". Colloquial usage of the term gene (e.g. "good genes, "hair color gene") mayactually refer to an allele: a gene is the basic instruction, a sequence of nucleic acid (DNA or, in thecase of certain viruses RNA), while an allele is one variant of that instruction

The notion of a gene is evolving with the science of genetics, which began when Gregor Mendelnoticed that biological variations are inherited from parent organisms as specific, discrete traits.The biological entity responsible for defining traits was later termed a gene, but the biological basisfor inheritance remained unknown until DNA was identified as the genetic material in the 1940s.All organisms have many genes corresponding to many different biological traits, some of whichare immediately visible, such as eye color or number of limbs, and some of which are not, such asblood type or increased risk for specific diseases, or the thousands of basic biochemical processesthat comprise life.



The vast majority of living organisms encode their genes in long strands of DNA. DNA(deoxyribonucleic acid) consists of a chain made from four types of nucleotide subunits, eachcomposed of: a five-carbon sugar (2'-deoxyribose), a phosphate group, and one of the four basesadenine, cytosine, guanine, and thymine. The most common form of DNA in a cell is in a doublehelix structure, in which two individual DNA strands twist around each other in a right-handedspiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adeninepairs with thymine. The base pairing between guanine and cytosine forms three hydrogen bonds,whereas the base pairing between adenine and thymine forms two hydrogen bonds. The two strandsin a double helix must therefore be complementary, that is, their bases must align such that theadenines of one strand are paired with the thymines of the other strand, and so on.

Due to the chemical composition of the pentose residues of the bases, DNA strands havedirectionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose;this is known as the 3' end of the molecule. The other end contains an exposed phosphate group;this is the 5' end. The directionality of DNA is vitally important to many cellular processes, sincedouble helices are necessarily directional (a strand running 5'-3' pairs with a complementary strandrunning 3'-5'), and processes such as DNA replication occur in only one direction. All nucleic acidsynthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydrationreaction that uses the exposed 3' hydroxyl as a nucleophile.

The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second typeof nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose ratherthan deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are lessstable than DNA and are typically single-stranded. Genes that encode proteins are composed of aseries of three-nucleotide sequences called codons, which serve as the words in the geneticlanguage. The genetic code specifies the correspondence during protein translation between codonsand amino acids. The genetic code is nearly the same for all known organisms.

RNA genes and genomes

When proteins are manufactured, the gene is first copied into RNA as an intermediate product. Inother cases, the RNA molecules are the actual functional products. For example, RNAs known asribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNAsequences from which such RNAs are transcribed are known as RNA genes.

Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Becausethey use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they areinfected and without the delay in waiting for transcription. On the other hand, RNA retroviruses,such as HIV, require the reverse transcription of their genome from RNA into DNA before theirproteins can be synthesized. In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mouse. Mice with a loss-of-function mutation in the gene Kit have whitetails. Offspring of these mutants can have white tails despite having only normal Kit genes. Theresearch team traced this effect back to mutated Kit RNA.[4] While RNA is common as geneticstorage material in viruses, in mammals in particular RNA inheritance has been observed veryrarely.



Functional structure of a gene

All genes have regulatory regions in addition to regions that explicitly code for a protein or RNAproduct. A regulatory region shared by almost all genes is known as the promoter, which provides aposition that is recognized by the transcription machinery when a gene is about to be transcribedand expressed. A gene can have more than one promoter, resulting in RNAs that differ in how farthey extend in the 5' end. Although promoter regions have a consensus sequence that is the mostcommon sequence at this position, some genes have "strong" promoters that bind the transcriptionmachinery well, and others have "weak" promoters that bind poorly. These weak promoters usuallypermit a lower rate of transcription than the strong promoters, because the transcription machinerybinds to them and initiates transcription less frequently. Other possible regulatory regions includeenhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream"—that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regionsare much more complex and difficult to identify than prokaryotic promoters.

Many prokaryotic genes are organized into operons, or groups of genes whose products haverelated functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribedonly one at a time, but may include long stretches of DNA called introns which are transcribed butnever translated into protein (they are spliced out before translation). Splicing can also occur inprokaryotic genes, but is less common than in eukaryotes.

Chromosomes

The total complement of genes in an organism or cell is known as its genome, which may be storedon one or more chromosomes; the region of the chromosome at which a particular gene is located iscalled its locus. A chromosome consists of a single, very long DNA helix on which thousands ofgenes are encoded. Prokaryotes—bacteria and archaea—typically store their genomes on a singlelarge, circular chromosome, sometimes supplemented by additional small circles of DNA calledplasmids, which usually encode only a few genes and are easily transferable between individuals.For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and canbe passed between individual cells, even those of different species, via horizontal gene transfer.Although some simple eukaryotes also possess plasmids with small numbers of genes, the majorityof eukaryotic genes are stored on multiple linear chromosomes, which are packed within thenucleus in complex with storage proteins called histones. The manner in which DNA is stored onthe histone, as well as chemical modifications of the histone itself, are regulatory mechanismsgoverning whether a particular region of DNA is accessible for gene expression. The ends ofeukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres,which do not code for any gene product but are present to prevent degradation of coding andregulatory regions during DNA replication. The length of the telomeres tends to decrease each timethe genome is replicated in preparation for cell division; the loss of telomeres has been proposed asan explanation for cellular senescence, or the loss of the ability to divide, and by extension for theaging process in organisms.

Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes oftencontain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas the genomes of complexmulticellular organisms, including humans, contain an absolute majority of DNA without anidentified function.[8] However it now appears that, although protein-coding DNA makes up barely



2% of the human genome, about 80% of the bases in the genome may be being expressed, so theterm "junk DNA" may be a misnomer.

Gene expression

In all organisms, there are two major steps separating a protein-coding gene from its protein: First,the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA);and, second, it must be translated from mRNA to protein. RNA-coding genes must still go throughthe first step, but are not translated into protein. The process of producing a biologically functionalmolecule of either RNA or protein is called gene expression, and the resulting molecule itself iscalled a gene product.

Genetic code

The genetic code is the set of rules by which a gene is translated into a functional protein. Eachgene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA) strand;a correspondence between nucleotides, the basic building blocks of genetic material, and aminoacids, the basic building blocks of proteins, must be established for genes to be successfullytranslated into functional proteins. Sets of three nucleotides, known as codons, each correspond to aspecific amino acid or to a signal; three codons are known as "stop codons" and, instead ofspecifying a new amino acid, alert the translation machinery that the end of the gene has beenreached. There are 64 possible codons (four possible nucleotides at each of three positions, hence43 possible codons) and only 20 standard amino acids; hence the code is redundant and multiplecodons can specify the same amino acid. The correspondence between codons and amino acids isnearly universal among all known living organisms.

Transcription

The process of genetic transcription produces a single-stranded RNA molecule known asmessenger RNA, whose nucleotide sequence is complementary to the DNA from which it wastranscribed. The DNA strand whose sequence matches that of the RNA is known as the codingstrand and the strand from which the RNA was synthesized is the template strand. Transcription isperformed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5'direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase firstrecognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation isthe blocking or sequestering of the promoter region, either by tight binding by repressor moleculesthat physically block the polymerase, or by organizing the DNA so that the promoter region is notaccessible.

In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation maybegin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes,transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNAmolecule produced by the polymerase is known as the primary transcript and must undergo post-transcriptional modifications before being exported to the cytoplasm for translation. The splicing ofintrons present within the transcribed region is a modification unique to eukaryotes; alternativesplicing mechanisms can result in mature transcripts from the same gene having different sequencesand thus coding for different proteins. This is a major form of regulation in eukaryotic cells.



Translation

Translation is the process by which a mature mRNA molecule is used as a template forsynthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA andprotein responsible for carrying out the chemical reactions to add new amino acids to a growingpolypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at atime, in units called codons, via interactions with specialized RNA molecules called transfer RNA(tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary tothe codon it reads; the tRNA is also covalently attached to the amino acid specified by thecomplementary codon. When the tRNA binds to its complementary codon in an mRNA strand, theribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized fromamino terminus to carboxyl terminus. During and after its synthesis, the new protein must fold to itsactive three-dimensional structure before it can carry out its cellular function.

DNA replication and inheritance

The growth, development, and reproduction of organisms relies on cell division, or the process bywhich a single cell divides into two usually identical daughter cells. This requires first making aduplicate copy of every gene in the genome in a process called DNA replication. The copies aremade by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Becausethe DNA double helix is held together by base pairing, the sequence of one strand completelyspecifies the sequence of its complement; hence only one strand needs to be read by the enzyme toproduce a faithful copy. The process of DNA replication is semiconservative; that is, the copy ofthe genome inherited by each daughter cell contains one original and one newly synthesized strandof DNA.

After DNA replication is complete, the cell must physically separate the two copies of the genomeand divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - thisusually occurs via a relatively simple process called binary fission, in which each circular genomeattaches to the cell membrane and is separated into the daughter cells as the membrane invaginatesto split the cytoplasm into two membrane-bound portions. Binary fission is extremely fastcompared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complexprocess known as the cell cycle; DNA replication occurs during a phase of this cycle known as Sphase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs duringM phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common,which results in asymmetrical portions of cytoplasm in the two daughter cells.

Molecular inheritance

The duplication and transmission of genetic material from one generation of cells to the next is thebasis for molecular inheritance, and the link between the classical and molecular pictures of genes.Organisms inherit the characteristics of their parents because the cells of the offspring containcopies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will bea genetic copy or clone of the parent organism. In sexually reproducing organisms, a specializedform of cell division called meiosis produces cells called gametes or germ cells that are haploid, orcontain only one copy of each gene. The gametes produced by females are called eggs or ova, andthose produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell



that once again has a diploid number of genes—each with one copy from the mother and one copyfrom the father.

During the process of meiotic cell division, an event called genetic recombination or crossing-overcan sometimes occur, in which a length of DNA on one chromatid is swapped with a length ofDNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids arethe same, but results in reassortment of otherwise linked alleles if they are different. The Mendelianprinciple of independent assortment asserts that each of a parent's two genes for each trait will sortindependently into gametes; which allele an organism inherits for one trait is unrelated to whichallele it inherits for another trait. This is in fact only true for genes that do not reside on the samechromosome, or are located very far from one another on the same chromosome. The closer twogenes lie on the same chromosome, the more closely they will be associated in gametes and themore often they will appear together; genes that are very close are essentially never separatedbecause it is extremely unlikely that a crossover point will occur between them. This is known asgenetic linkage.

History

Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, whichproposes that the traits of the parents blend or mix in a smooth, continuous gradient in theoffspring. Although Mendel's work was largely unrecognized after its first publication in 1866, itwas rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich vonTschermak, who had reached similar conclusions from their own research. However, thesescientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.

The existence of genes was first suggested by Gregor Mendel (1822–1884), who, in the 1860s,studied inheritance in peaplants (Pisum sativum) and hypothesized a factor that conveys traits fromparent to offspring. He spent over 10 years of his life on one experiment. Although he did not usethe term gene, he explained his results in terms of inherited characteristics. Mendel was also thefirst to hypothesize independent assortment, the distinction between dominant and recessive traits,the distinction between a heterozygote and homozygote, and the difference between what wouldlater be described as genotype (the genetic material of an organism) and phenotype (the visibletraits of that organism). Mendel's concept was given a name by Hugo de Vries in 1889, who, at thattime probably unaware of Mendel's work, in his book Intracellular Pangenesis coined the term"pangen" for "the smallest particle [representing] one hereditary characteristic".

Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would laterbecome known as Chromosomes had been observed separating out during cell division by WilhelmHofmeister as early as 1848. The idea that chromosomes are the carriers of inheritance wasexpressed in 1883 by Wilhelm Roux. The modern conception of the gene originated with work byGregor Mendel, a 19th-century Augustinian monk who systematically studied heredity in peaplants. Mendel's work was the first to illustrate particulate inheritance, or the theory that inheritedtraits are passed from one generation to the next in discrete units that interact in well-defined ways.Danish botanist Wilhelm Johannsen coined the word "gene" ("gen" in Danish and German) in 1909to describe these fundamental physical and functional units of heredity, while the related wordgenetics was first used by William Bateson in 1905.The word was derived from Hugo de Vries'1889 term pangen for the same concept, itself a derivative of the word pangenesis coined by



Darwin (1868). The word pangenesis is made from the Greek words pan (a prefix meaning"whole", "encompassing") and genesis ("birth") or genos ("origin").

In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, ThomasHunt Morgan showed that genes reside on specific chromosomes. He later showed that genesoccupy specific locations on the chromosome. With this knowledge, Morgan and his students beganthe first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed thatgenes could be transferred. In what is now known as Griffith's experiment, injections into a mouseof a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe

strain of the same bacteria, killing the mouse.

A series of subsequent discoveries led to the realization decades later that chromosomes withincells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), apolymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance areencoded.

In 1941, George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes causederrors in specific steps in metabolic pathways. This showed that specific genes code for specificproteins, leading to the "one gene, one enzyme" hypothesis. Oswald Avery, Colin Munro MacLeod,and Maclyn McCarty showed in 1944 that DNA holds the gene's information. In 1953, James D.Watson and Francis Crick demonstrated the molecular structure of DNA. Together, thesediscoveries established the central dogma of molecular biology, which states that proteins aretranslated from RNA which is transcribed from DNA. This dogma has since been shown to haveexceptions, such as reverse transcription in retroviruses.

In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University ofGhent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene forBacteriophage MS2 coat protein.Richard J. Roberts and Phillip Sharp discovered in 1977 that genescan be split into segments. This led to the idea that one gene can make several proteins. Recently(as of 2003–2006), biological results let the notion of gene appear more slippery. In particular,genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNAproducing distinct proteins may overlap, so that the idea emerges that "genes are one longcontinuum".

It was first hypothesized in 1986 by Walter Gilbert that neither DNA nor protein would be requiredin such a primitive system as that of a very early stage of the earth if RNA could perform as simplya catalyst and genetic information storage processor.

The modern study of genetics at the level of DNA is known as molecular genetics and the synthesisof molecular genetics with traditional Darwinian evolution is known as the modern evolutionarysynthesis.

Mendelian inheritance and classical genetics

According to the theory of Mendelian inheritance, variations in phenotype—the observablephysical and behavioral characteristics of an organism—are due to variations in genotype, or theorganism's particular set of genes, each of which specifies a particular trait. Different forms of a



gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the peaplants Mendel worked on, along with many plants and animals, have two alleles for each trait, oneinherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to theircorresponding phenotypes when paired with any other allele for the same trait, whereas recessivealleles give rise to their corresponding phenotype only when paired with another copy of the sameallele. For example, if the allele specifying tall stems in pea plants is dominant over the allelespecifying short stems, then pea plants that inherit one tall allele from one parent and one shortallele from the other parent will also have tall stems. Mendel's work found that alleles assortindependently in the production of gametes, or germ cells, ensuring variation in the next generation.

Mutation

DNA replication is for the most part extremely accurate, with an error rate per site of around 10−6to 10−10 in eukaryotes.[9] Rare, spontaneous alterations in the base sequence of a particular genearise from a number of sources, such as errors in DNA replication and the aftermath of DNAdamage. These errors are called mutations. The cell contains many DNA repair mechanisms forpreventing mutations and maintaining the integrity of the genome; however, in some cases—suchas breaks in both DNA strands of a chromosome — repairing the physical damage to the moleculeis a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, somemutations in protein-coding genes are silent, or produce no change in the amino acid sequence ofthe protein for which they code; for example, the codons UCU and UUC both code for serine, sothe U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are mostoften neutral or deleterious to the organism, but sometimes they confer benefits to the organism'sfitness.

Mutations propagated to the next generation lead to variations within a species' population.Variants of a single gene are known as alleles, and differences in alleles may give rise todifferences in traits. Although it is rare for the variants in a single gene to have clearlydistinguishable phenotypic effects, certain well-defined traits are in fact controlled by single geneticloci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants.However, this does not imply that the wild-type allele is the ancestor from which the mutants aredescended.

Genome

Chromosomal organization

The total complement of genes in an organism or cell is known as its genome. In prokaryotes, thevast majority of genes are located on a single chromosome of circular DNA, while eukaryotesusually possess multiple individual linear DNA helices packed into dense DNA-protein complexescalled chromosomes. Genes that appear together on one chromosome of one species may appear onseparate chromosomes in another species. Many species carry more than one copy of their genomewithin each of their somatic cells. Cells or organisms with only one copy of each chromosome arecalled haploid; those with two copies are called diploid; and those with more than two copies arecalled polyploid. The copies of genes on the chromosomes are not necessarily identical. In sexuallyreproducing organisms, one copy is normally inherited from each parent.



Number of genes

Early estimates of the number of human genes that used expressed sequence tag data put it at 50000–100 000. Following the sequencing of the human genome and other genomes, it has beenfound that rather few genes (~20 000 in human, mouse and fly, ~13 000 in roundworm, >46 000 inrice) encode all the proteins in an organism. These protein-coding sequences make up 1–2% of thehuman genome.[18] A large part of the genome is transcribed however, to introns, retrotransposonsand seemingly a large array of noncoding RNAs.

Genetic and genomic nomenclature

Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC)for each known human gene in the form of an approved gene name and symbol (short-formabbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique andeach gene is only given one approved gene symbol. It is necessary to provide a unique symbol foreach gene so that people can talk about them. This also facilitates electronic data retrieval frompublications. In preference each symbol maintains parallel construction in different members of agene family and can be used in other species, especially the mouse.

Evolutionary concept of a gene

George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 bookAdaptation and Natural Selection. He proposed an evolutionary concept of gene to be used whenwe are talking about natural selection favoring some genes. The definition is: "that whichsegregates and recombines with appreciable frequency." According to this definition, even anasexual genome could be considered a gene, insofar that it have an appreciable permanency throughmany generations.

The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as aunit.

Richard Dawkins' books The Selfish Gene (1976) and The Extended Phenotype (1982) defendedthe idea that the gene is the only replicator in living systems. This means that only genes transmittheir structure largely intact and are potentially immortal in the form of copies. So, genes should bethe unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "aninheritable unit" instead of the generally accepted definition of "a section of DNA coding for aparticular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selectionby describing life as a river of compatible genes flowing through geological time. Scoop up abucket of genes from the river of genes, and we have an organism serving as temporary bodies orsurvival machines. A river of genes may fork into two branches representing two non-interbreedingspecies as a result of geographical separation.

Gene targeting and implications

Gene targeting is commonly referred to techniques for altering or disrupting mouse genes andprovides the mouse models for studying the roles of individual genes in embryonic development,human disorders, aging and diseases. The mouse models, where one or more of its genes aredeactivated or made inoperable, are called knockout mice. Since the first reports in which



homologous recombination in embryonic stem cells was used to generate gene-targeted mice, genetargeting has proven to be a powerful means of precisely manipulating the mammalian genome,producing at least ten thousand mutant mouse strains and it is now possible to introduce mutationsthat can be activated at specific time points, or in specific cells or organs, both during developmentand in the adult animal.

Gene targeting strategies have been expanded to all kinds of modifications, including pointmutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertionand deletion, tissue specific disruption combined with spatial and temporal regulation and so on. Itis predicted that the ability to generate mouse models with predictable phenotypes will have amajor impact on studies of all phases of development, immunology, neurobiology, oncology,physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to speciesfrom which toti potent embryonic stem cells can be established, and therefore may offer a potentialto the improvement of domestic animals and plants.

Changing concept

The concept of the gene has changed considerably (see history section). From the originaldefinition of a "unit of inheritance", the term evolved to mean a DNA-based unit that can exert itseffects on the organism through RNA or protein products. It was also previously believed that onegene makes one protein; this concept was overthrown by the discovery of alternative splicing andtrans-splicing.

The definition of a gene is still changing. The first cases of RNA-based inheritance have beendiscovered in mammals. Evidence is also accumulating that the control regions of a gene do notnecessarily have to be close to the coding sequence on the linear molecule or even on the samechromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus onchromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.

The concept that genes are clearly delimited is also being eroded. There is evidence for fusedproteins stemming from two adjacent genes that can produce two separate protein products. Whileit is not clear whether these fusion proteins are functional, the phenomenon is more frequent thanpreviously thought. Even more ground-breaking than the discovery of fused genes is theobservation that some proteins can be composed of exons from far away regions and even differentchromosomes. This new data has led to an updated, and probably tentative, definition of a gene as"a union of genomic sequences encoding a coherent set of potentially overlapping functionalproducts." This new definition categorizes genes by functional products, whether they be proteinsor RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified asgene-associated regions.

Evolutionary Basis of Behaviour

Evolution of behaviour is based on the premise that some behaviors (both social and individual) areat least partly inherited and can be affected by natural selection. It begins with the idea thatbehaviors have evolved over time, similar to the way that physical traits are thought to haveevolved. It predicts therefore that animals will act in ways that have proven to be evolutionarily



successful over time, which can among other things result in the formation of complex socialprocesses conducive to evolutionary fitness.

The discipline seeks to explain behavior as a product of natural selection. Behavior is thereforeseen as an effort to preserve one's genes in the population. Inherent in sociobiological reasoning isthe idea that certain genes or gene combinations that influence particular behavioral traits can beinherited from generation to generation.

Introductory examples

For example, newly dominant male lions often will kill cubs in the pride that were not sired bythem. This behaviour is adaptive in evolutionary terms because killing the cubs eliminatescompetition for their own offspring and causes the nursing females to come into heat faster, thusallowing more of his genes to enter into the population. Sociobiologists would view this instinctualcub-killing behavior as being inherited through the genes of successfully reproducing male lions,whereas non-killing behaviour may have "died out" as those lions were less successful inreproducing.

Genetic mouse mutants have now been harnessed to illustrate the power that genes exert onbehaviour. For example, the transcription factor FEV (aka Pet1) has been shown, through its role inmaintaining the serotonergic system in the brain, to be required for normal aggressive and anxiety-like behavior. Thus, when FEV is genetically deleted from the mouse genome, male mice willinstantly attack other males, whereas their wild-type counterparts take significantly longer toinitiate violent behaviour. In addition, FEV has been shown to be required for correct maternalbehaviour in mice, such that their offspring do not survive unless cross-fostered to other wild-typefemale mice

A genetic basis for instinctive behavioural traits among non-human species, such as in the aboveexample, is commonly accepted among many biologists; however, attempting to use a genetic basisto explain complex behaviours in human societies has remained extremely controversial.

History

According to the OED, John Paul Scott coined the word "sociobiology" at a 1946 conference ongenetics and social behaviour, and became widely used after it was popularized by Edward O.Wilson in his 1975 book, Sociobiology: The New Synthesis. However, the influence of evolution onbehavior has been of interest to biologists and philosophers since soon after the discovery of theevolution itself. Peter Kropotkin's Mutual Aid: A Factor of Evolution, written in the early 1890s, isa popular example. Antecedents of modern sociobiological thinking can be traced to the 1960s andthe work of such biologists as Robert Trivers and William D. Hamilton.

Nonetheless, it was Wilson's book that pioneered and popularized the attempt to explain theevolutionary mechanics behind social behaviors such as altruism, aggression, and nurturence,primarily in ants (Wilson's own research specialty) but also in other animals. The final chapter ofthe book is devoted to sociobiological explanations of human behavior, and Wilson later wrote aPulitzer Prize winning book, On Human Nature, that addressed human behavior specifically.



Sociobiological theory

Sociobiologists believe that human behavior, as well as nonhuman animal behavior, can be partlyexplained as the outcome of natural selection. They contend that in order fully to understandbehavior, it must be analyzed in terms of evolutionary considerations.

Natural selection is fundamental to evolutionary theory. Variants of hereditary traits which increasean organism's ability to survive and reproduce will be more greatly represented in subsequentgenerations, i.e., they will be "selected for". Thus, inherited behavioral mechanisms that allowed anorganism a greater chance of surviving and/or reproducing in the past are more likely to survive inpresent organisms. That inherited adaptive behaviors are present in nonhuman animal species hasbeen multiply demonstrated by biologists, and it has become a foundation of evolutionary biology.However, there is continued resistance by some researchers over the application of evolutionarymodels to humans, particularly from within the social sciences, where culture has long beenassumed to be the predominant driver of behavior.

Sociobiology is based upon two fundamental premises:

Certain behavioral traits are inherited,

Inherited behavioral traits have been honed by natural selection. Therefore, these traits wereprobably "adaptive" in the species` evolutionarily evolved environment.

Sociobiology uses Nikolaas Tinbergen's four categories of questions and explanations of animalbehavior. Two categories are at the species level; two, at the individual level. The species-levelcategories (often called “ultimate explanations”) are

the function (i.e., adaptation) that a behavior serves and

the evolutionary process (i.e., phylogeny) that resulted in this functionality.

The individual-level categories (often called “proximate explanations”) are

the development of the individual (i.e., ontogeny) and

the proximate mechanism (e.g., brain anatomy and hormones).

Sociobiologists are interested in how behavior can be explained logically as a result ofselective pressures in the history of a species. Thus, they are often interested in instinctive, orintuitive behavior, and in explaining the similarities, rather than the differences, between cultures.For example, mothers within many species of mammals – including humans – are very protectiveof their offspring. Sociobiologists reason that this protective behavior likely evolved over timebecause it helped those individuals which had the characteristic to survive and reproduce. Overtime, individuals who exhibited such protective behaviours would have had more survivingoffspring than did those who did not display such behaviours, such that this parental protectionwould increase in frequency in the population. In this way, the social behavior is believed to haveevolved in a fashion similar to other types of nonbehavioral adaptations, such as (for example) furor the sense of smell.



Individual genetic advantage often fails to explain certain social behaviors as a result of gene-centred selection, and evolution may also act upon groups. The mechanisms responsible for groupselection employ paradigms and population statistics borrowed from game theory. E.O. Wilsonargued that altruistic individuals must reproduce their own altruistic genetic traits for altruism tosurvive. When altruists lavish their resources on non-altruists at the expense of their own kind, thealtruists tend to die out and the others tend to grow. In other words, altruism is more likely tosurvive if altruists practice the ethic that "charity begins at home."

Within sociobiology, a social behavior is first explained as a sociobiological hypothesis by findingan evolutionarily stable strategy that matches the observed behavior. Stability of a strategy can bedifficult to prove, but usually, a well-formed strategy will predict gene frequencies. The hypothesiscan be supported by establishing a correlation between the gene frequencies predicted by thestrategy, and those expressed in a population. Measurement of genes and gene-frequencies can beproblematic, however, because a simple statistical correlation can be open to charges of circularity(Circularity can occur if the measurement of gene frequency indirectly uses the same measurementsthat describe the strategy).

Altruism between social insects and littermates has been explained in such a way. Altruisticbehavior in some animals has been correlated to the degree of genome shared between altruisticindividuals. A quantitative description of infanticide by male harem-mating animals when the alphamale is displaced as well as rodent female infanticide and fetal resorption are active areas of study.In general, females with more bearing opportunities may value offspring less, and may also arrangebearing opportunities to maximize the food and protection from mates.

An important concept in sociobiology is that temperamental traits within a gene pool and betweengene pools exist in an ecological balance. Just as an expansion of a sheep population mightencourage the expansion of a wolf population, an expansion of altruistic traits within a gene poolmay also encourage the expansion of individuals with dependent traits.

Sociobiology is sometimes associated with arguments over the "genetic" basis of intelligence.While sociobiology is predicated on the observation that genes do affect behavior, it is perfectlyconsistent to be a sociobiologist while arguing that measured IQ variations between individualsreflect mainly cultural or economic rather than genetic factors. However, many critics point out thatthe usefulness of sociobiology as an explanatory tool breaks down once a trait is so variable as tono longer be exposed to selective pressures. In order to explain aspects of human intelligence as theoutcome of selective pressures, it must be demonstrated that those aspects are inherited, or genetic,but this does not necessarily imply differences among individuals: a common genetic inheritancecould be shared by all humans, just as the genes responsible for number of limbs are shared by allindividuals. An even more sensitive subject is race and intelligence.

Researchers performing twin studies have argued that differences between people on behavioraltraits such as creativity, extroversion and aggressiveness are between 45% to 75% due to geneticdifferences, and intelligence is said by some to be about 80% genetic after one matures (discussedat Intelligence quotient#Environment). However, critics (such as the evolutionary geneticist R. CLewontin) have highlighted serious flaws in twin studies, such as the inability of researchers toseparate environmental, genetic, and dialectic effects on twins.



Criminality is actively under study, but extremely controversial. There are arguments that in someenvironments criminal behavior might be adaptive.

Criticism

Many critics draw an intellectual link between sociobiology and biological determinism, the beliefthat most human differences can be traced to specific genes rather than differences in culture orsocial environments. Critics also draw parallels between biological determinism as an underlyingphilosophy to the social Darwinian and eugenics movements of the early 20th century, andcontroversies in the history of intelligence testing. Steven Pinker argues that critics have beenoverly swayed by politics and a "fear" of biological determinism. However, all these critics haveclaimed that sociobiology fails on scientific grounds, independent of their political critiques. Inparticular, Lewontin, Rose & Kamin drew a detailed distinction between the politics and history ofan idea and its scientific validity, as has Stephen Jay Gould.

Wilson and his supporters counter the intellectual link by denying that Wilson had a politicalagenda, still less a right-wing one. They pointed out that Wilson had personally adopted a numberof liberal political stances and had attracted progressive sympathy for his outspokenenvironmentalism. They argued that as scientists they had a duty to uncover the truth whether thatwas politically correct or not. They argued that sociobiology does not necessarily lead to anyparticular political ideology as many critics implied. Many subsequent sociobiologists, includingRobert Wright, Anne Campbell, Frans de Waal and Sarah Blaffer Hrdy, have used sociobiology toargue quite separate points. Noam Chomsky came to the defense of sociobiology's methodology,noting that it was the same methodology he used in his work on linguistics. However, he roundlycriticized the sociobiologists' actual conclusions about humans as lacking substance. He also notedthat the anarchist Peter Kropotkin had made similar arguments in his book Mutual Aid: A Factor ofEvolution, although focusing more on altruism than aggression, suggesting that anarchist societieswere feasible because of an innate human tendency to cooperate.

Wilson's claims that he had never meant to imply what ought to be, only what is the case aresupported by his writings, which are descriptive, not prescriptive. However, many critics havepointed out that the language of sociobiology often slips from "is" to "ought",leadingsociobiologists to make arguments against social reform on the basis that socially progressivesocieties are at odds with our innermost nature. For example, some groups have supported positionsof ethnic nepotism. Views such as this, however, are often criticized as examples of the naturalisticfallacy, when reasoning jumps from descriptions about what is to prescriptions about what ought tobe. (A common example is the justification of militarism if scientific evidence showed warfare waspart of human nature.) It has also been argued that opposition to stances considered anti-social,such as ethnic nepotism, are based on moral assumptions, not bioscientific assumptions, meaningthat it is not vulnerable to being disproved by bioscientific advances. The history of this debate, andothers related to it, are covered in detail by Cronin (1992), Segerstråle (2000) and Alcock (2001).Adaptationists such as Steven Pinker have also suggested that the debate has a strong ad hominemcomponent.



Module 3

THE NEURON

Structure Function and Types of Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical andchemical signaling. Chemical signaling occurs via synapses, specialized connections with othercells. Neurons connect to each other to form networks. Neurons are the core components of thenervous system, which includes the brain, spinal cord, and peripheral ganglia. A number ofspecialized types of neurons exist: sensory neurons respond to touch, sound, light and numerousother stimuli affecting cells of the sensory organs that then send signals to the spinal cord and brain.Motor neurons receive signals from the brain and spinal cord and cause muscle contractions andaffect glands. Interneurons connect neurons to other neurons within the same region of the brain orspinal cord.

A typical neuron possesses a cell body (often called the soma), dendrites, and an axon. Dendritesare filaments that arise from the cell body, often extending for hundreds of microns and branchingmultiple times, giving rise to a complex "dendritic tree". An axon is a special cellular filament thatarises from the cell body at a site called the axon hillock and travels for a distance, as far as 1 m inhumans or even more in other species. The cell body of a neuron frequently gives rise to multipledendrites, but never to more than one axon, although the axon may branch hundreds of times beforeit terminates. At the majority of synapses, signals are sent from the axon of one neuron to a dendriteof another. There are, however, many exceptions to these rules: neurons that lack dendrites,neurons that have no axon, synapses that connect an axon to another axon or a dendrite to anotherdendrite, etc.

All neurons are electrically excitable, maintaining voltage gradients across their membranes bymeans of metabolically driven ion pumps, which combine with ion channels embedded in themembrane to generate intracellular-versus-extracellular concentration differences of ions such assodium, potassium, chloride, and calcium. Changes in the cross-membrane voltage can alter thefunction of voltage-dependent ion channels. If the voltage changes by a large enough amount, anall-or-none electrochemical pulse called an action potential is generated, which travels rapidlyalong the cell's axon, and activates synaptic connections with other cells when it arrives.

Neurons of the adult brain do not generally undergo cell division, and usually cannot be replacedafter being lost, although there are a few known exceptions. In most cases they are generated byspecial types of stem cells, although astrocytes (a type of glial cell) have been observed to turn intoneurons as they are sometimes pluripotent.

Overview

A neuron is a special type of cell that is found in the bodies of most animals (all members of thegroup Eumetazoa, to be precise—this excludes only sponges and a few other very simple animals).The features that define a neuron are electrical excitability and the presence of synapses, which arecomplex membrane junctions used to transmit signals to other cells. The body's neurons, plus theglial cells that give them structural and metabolic support, together constitute the nervous system.In vertebrates, the majority of neurons belong to the central nervous system, but some reside in



peripheral ganglia, and many sensory neurons are situated in sensory organs such as the retina andcochlea.

Although neurons are very diverse and there are exceptions to nearly every rule, it is convenient tobegin with a schematic description of the structure and function of a "typical" neuron. A typicalneuron is divided into three parts: the soma or cell body, dendrites, and axon. The soma is usuallycompact; the axon and dendrites are filaments that extrude from it. Dendrites typically branchprofusely, getting thinner with each branching, and extending their farthest branches a few hundredmicrons from the soma. The axon leaves the soma at a swelling called the axon hillock, and canextend for great distances, giving rise to hundreds of branches. Unlike dendrites, an axon usuallymaintains the same diameter as it extends. The soma may give rise to numerous dendrites, butnever to more than one axon. Synaptic signals from other neurons are received by the soma anddendrites; signals to other neurons are transmitted by the axon. A typical synapse, then, is a contactbetween the axon of one neuron and a dendrite or soma of another. Synaptic signals may beexcitatory or inhibitory. If the net excitation received by a neuron over a short period of time islarge enough, the neuron generates a brief pulse called an action potential, which originates at thesoma and propagates rapidly along the axon, activating synapses onto other neurons as it goes.

Many neurons fit the foregoing schema in every respect, but there are also exceptions to most partsof it. There are no neurons that lack a soma, but there are neurons that lack dendrites, and othersthat lack an axon. Furthermore, in addition to the typical axodendritic and axosomatic synapses,there are axoaxonic (axon-to-axon) and dendrodendritic (dendrite-to-dendrite) synapses.

The key to neural function is the synaptic signalling process, which is partly electrical and partlychemical. The electrical aspect depends on properties of the neuron's membrane. Like all animalcells, every neuron is surrounded by a plasma membrane, a bilayer of lipid molecules with manytypes of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator, but inneurons, many of the protein structures embedded in the membrane are electrically active. Theseinclude ion channels that permit electrically charged ions to flow across the membrane, and ionpumps that actively transport ions from one side of the membrane to the other. Most ion channelsare permeable only to specific types of ions. Some ion channels are voltage gated, meaning thatthey can be switched between open and closed states by altering the voltage difference across themembrane. Others are chemically gated, meaning that they can be switched between open andclosed states by interactions with chemicals that diffuse through the extracellular fluid. Theinteractions between ion channels and ion pumps produce a voltage difference across themembrane, typically a bit less than 1/10 of a volt at baseline. This voltage has two functions: first, itprovides a power source for an assortment of voltage-dependent protein machinery that isembedded in the membrane; second, it provides a basis for electrical signal transmission betweendifferent parts of the membrane.

Neurons communicate by chemical and electrical synapses in a process known as synaptictransmission. The fundamental process that triggers synaptic transmission is the action potential, apropagating electrical signal that is generated by exploiting the electrically excitable membrane ofthe neuron. This is also known as a wave of depolarization.



Anatomy and histology

Neurons are highly specialized for the processing and transmission of cellular signals. Given thediversity of functions performed by neurons in different parts of the nervous system, there is, asexpected, a wide variety in the shape, size, and electrochemical properties of neurons. For instance,the soma of a neuron can vary from 4 to 100 micrometers in diameter.

* The soma is the central part of the neuron. It contains the nucleus of the cell, and therefore iswhere most protein synthesis occurs. The nucleus ranges from 3 to 18 micrometers in diameter.

* The dendrites of a neuron are cellular extensions with many branches, and metaphorically thisoverall shape and structure is referred to as a dendritic tree. This is where the majority of input tothe neuron occurs.

* The axon is a finer, cable-like projection which can extend tens, hundreds, or even tens ofthousands of times the diameter of the soma in length. The axon carries nerve signals away fromthe soma (and also carries some types of information back to it). Many neurons have only one axon,but this axon may—and usually will—undergo extensive branching, enabling communication withmany target cells. The part of the axon where it emerges from the soma is called the axon hillock.Besides being an anatomical structure, the axon hillock is also the part of the neuron that has thegreatest density of voltage-dependent sodium channels. This makes it the most easily-excited partof the neuron and the spike initiation zone for the axon: in electrophysiological terms it has themost negative action potential threshold. While the axon and axon hillock are generally involved ininformation outflow, this region can also receive input from other neurons.

* The axon terminal contains synapses, specialized structures where neurotransmitter chemicalsare released in order to communicate with target neurons.

Although the canonical view of the neuron attributes dedicated functions to its various anatomicalcomponents, dendrites and axons often act in ways contrary to their so-called main function.

Axons and dendrites in the central nervous system are typically only about one micrometer thick,while some in the peripheral nervous system are much thicker. The soma is usually about 10–25micrometers in diameter and often is not much larger than the cell nucleus it contains. The longestaxon of a human motoneuron can be over a meter long, reaching from the base of the spine to thetoes. Sensory neurons have axons that run from the toes to the dorsal columns, over 1.5 meters inadults. Giraffes have single axons several meters in length running along the entire length of theirnecks. Much of what is known about axonal function comes from studying the squid giant axon, anideal experimental preparation because of its relatively immense size (0.5–1 millimeters thick,several centimeters long).

Fully differentiated neurons are permanently amitotic; however, recent research shows thatadditional neurons throughout the brain can originate from neural stem cells found throughout thebrain but in particularly high concentrations in the subventricular zone and subgranular zonethrough the process of neurogenesis.



Histology and internal structure

Nerve cell bodies stained with basophilic dyes show numerous microscopic clumps of Nisslsubstance (named after German psychiatrist and neuropathologist Franz Nissl, 1860–1919), whichconsists of rough endoplasmic reticulum and associated ribosomal RNA. The prominence of theNissl substance can be explained by the fact that nerve cells are metabolically very active, andhence are involved in large amounts of protein synthesis.

The cell body of a neuron is supported by a complex meshwork of structural proteins calledneurofilaments, which are assembled into larger neurofibrils. Some neurons also contain pigmentgranules, such as neuromelanin (a brownish-black pigment, byproduct of synthesis ofcatecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).

There are different internal structural characteristics between axons and dendrites. Typical axonsalmost never contain ribosomes, except some in the initial segment. Dendrites contain granularendoplasmic reticulum or ribosomes, with diminishing amounts with distance from the cell body.

Classes

Neurons exist in a number of different shapes and sizes and can be classified by their morphologyand function. The anatomist Camillo Golgi grouped neurons into two types; type I with long axonsused to move signals over long distances and type II with short axons, which can often be confusedwith dendrites. Type I cells can be further divided by where the cell body or soma is located. Thebasic morphology of type I neurons, represented by spinal motor neurons, consists of a cell bodycalled the soma and a long thin axon which is covered by the myelin sheath. Around the cell bodyis a branching dendritic tree that receives signals from other neurons. The end of the axon hasbranching terminals (axon terminal) that release neurotransmitters into a gap called the synapticcleft between the terminals and the dendrites of the next neuron.

Structural classification

Polarity

Most neurons can be anatomically characterized as:

* Unipolar or pseudounipolar: dendrite and axon emerging from same process.

* Bipolar: axon and single dendrite on opposite ends of the soma.

* Multipolar: more than two dendrites:

o Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinjecells, and anterior horn cells.

o Golgi II: neurons whose axonal process projects locally; the best example is the granule cell.

Other

Furthermore, some unique neuronal types can be identified according to their location in thenervous system and distinct shape. Some examples are:



* Basket cells, interneurons that form a dense plexus of terminals around the soma of target cells,found in the cortex and cerebellum.

* Betz cells, large motor neurons.* Medium spiny neurons, most neurons in the corpus striatum.* Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar neuron.* Pyramidal cells, neurons with triangular soma, a type of Golgi I.* Renshaw cells, neurons with both ends linked to alpha motor neurons.* Granule cells, a type of Golgi II neuron.* anterior horn cells, motoneurons located in the spinal cord.

Functional classification

Direction

* Afferent neurons convey information from tissues and organs into the central nervous systemand are sometimes also called sensory neurons.

* Efferent neurons transmit signals from the central nervous system to the effector cells and aresometimes called motor neurons.

* Interneurons connect neurons within specific regions of the central nervous system.

Afferent and efferent can also refer generally to neurons which, respectively, bring information toor send information from the brain region.

Action on other neurons

A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors.The effect upon the target neuron is determined not by the source neuron or by theneurotransmitter, but by the type of receptor that is activated. A neurotransmitter can be thought ofas a key, and a receptor as a lock: the same type of key can here be used to open many differenttypes of locks. Receptors can be classified broadly as excitatory (causing an increase in firing rate),inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting effects notdirectly related to firing rate).

In fact, however, the two most common neurotransmitters in the brain, glutamate and GABA, haveactions that are largely consistent. Glutamate acts on several different types of receptors, but mostof them have effects that are excitatory. Similarly GABA acts on several different types ofreceptors, but all of them have effects (in adult animals, at least) that are inhibitory. Because of thisconsistency, it is common for neuroscientists to simplify the terminology by referring to cells thatrelease glutamate as "excitatory neurons," and cells that release GABA as "inhibitory neurons."Since well over 90% of the neurons in the brain release either glutamate or GABA, these labelsencompass the great majority of neurons. There are also other types of neurons that have consistenteffects on their targets, for example "excitatory" motor neurons in the spinal cord that releaseacetylcholine, and "inhibitory" spinal neurons that release glycine.

The distinction between excitatory and inhibitory neurotransmitters is not absolute, however.Rather, it depends on the class of chemical receptors present on the target neuron. In principle, asingle neuron, releasing a single neurotransmitter, can have excitatory effects on some targets,inhibitory effects on others, and modulatory effects on others still. For example, photoreceptors in



the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFFbipolar cells are, like most neurons, excited by the released glutamate. However, neighboring targetneurons called ON bipolar cells are instead inhibited by glutamate, because they lack the typicalionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamatereceptors. When light is present, the photoreceptors cease releasing glutamate, which relieves theON bipolar cells from inhibition, activating them; this simultaneously removes the excitation fromthe OFF bipolar cells, silencing them.

Discharge patterns

Neurons can be classified according to their electrophysiological characteristics:

* Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example:interneurons in neurostriatum.

* Phasic or bursting. Neurons that fire in bursts are called phasic.* Fast spiking. Some neurons are notable for their fast firing rates, for example some types of

cortical inhibitory interneurons, cells in globus pallidus, retinal ganglion cells.

Classification by neurotransmitter production

Neurons differ in the type of neurotransmitter they manufacture. Some examples are

* Cholinergic Neurons - acetylcholine

Acetylcholine is released from presynaptic neurons into the synaptic cleft. It acts as a ligand forboth ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinicreceptors, are pentameric ligand-gated ion channels composed of alpha and beta subunits that bindnicotine. Ligand binding opens the channel causing influx of Na+ depolarization and increases theprobability of presynaptic neurotransmitter release.

* GABAergic neurons - gamma aminobutyric acid

GABA is one of two neuroinhibitors in the CNS, the other being Glycine. GABA has ahomologous function to ACh, gating anion channels that allow Cl- ions to enter the post synapticneuron. Cl- causes hyperpolarization within the neuron, decreasing the probability of an actionpotential firing as the voltage becomes more negative (recall that for an action potential to fire, apositive voltage threshold must be reached).

* Glutamatergic Neurons - glutamate

Glutamate is one of two primary excitatory amino acids, the other being Aspartate. Glutamatereceptors are one of four categories, three of which are ligand-gated ion channels and one of whichis a G-protein coupled receptor (often referred to as GPCR). 1 - AMPA and Kainate receptors bothfunction as cation channels permeable to Na+ cation channels mediating fast excitatory synaptictransmission 2 - NMDA receptors are another cation channel that is more permeable to Ca2+. Thefunction of NMDA receptors is dependant on Glycine receptor binding as a co-agonist within thechannel pore. NMDA receptors will not function without both ligands present. 3 - Metabotropicreceptors, GPCRs modulate synaptic transmission and postsynaptic excitability. Glutamate can



cause excitotoxicity when blood flow to the brain is interrupted, resulting in brain damage. Whenblood flow is suppressed, glutamate is released from presynaptic neurons causing NMDA andAMPA receptor activation moreso than would normally be the case outside of stress conditions,leading to elevated Ca2+ and Na+ entering the post synaptic neuron and cell damage.

* dopaminergic neurons - dopamine

Dopamine is a neurotransmitter that acts on D1 type (D1 and D5) Gs coupled receptors whichincrease cAMP and PKA or D2 type (D2,D3 and D4)receptors which activate Gi-coupled receptorsthat decrease cAMP and PKA. Dopamine is connected to mood and behavior, and modulates bothpre and post synaptic neurotransmission. Loss of dopamine neurons in the substantia nigra has beenlinked to Parkinson's disease.

* Serotonergic Neurons - serotonin

Serotonin,(5-Hydroxytryptamine, 5-HT), can act as excitatory or inhibitory. Of the four 5-HTreceptor classes, 3 are GPCR and 1 is ligand gated cation channel. Serotonin is synthesized fromtryptophan by tryptophan hydroxylase, and then further by aromatic acid decarboxylase. A lack of5-HT at postsynaptic neurons has been linked to depression. Drugs that block the presynapticserotonin transporter are used for treatment, such as Prozac and Zoloft.

Connectivity

Neurons communicate with one another via synapses, where the axon terminal or en passantboutons (terminals located along the length of the axon) of one cell impinges upon another neuron'sdendrite, soma or, less commonly, axon. Neurons such as Purkinje cells in the cerebellum can haveover 1000 dendritic branches, making connections with tens of thousands of other cells; otherneurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or twodendrites, each of which receives thousands of synapses. Synapses can be excitatory or inhibitoryand will either increase or decrease activity in the target neuron. Some neurons also communicatevia electrical synapses, which are direct, electrically-conductive junctions between cells.

In a chemical synapse, the process of synaptic transmission is as follows: when an action potentialreaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enterthe terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse withthe membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse acrossthe synaptic cleft and activate receptors on the postsynaptic neuron.

The human brain has a huge number of synapses. Each of the 1011 (one hundred billion) neuronshas on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of athree-year-old child has about 1015 synapses (1 quadrillion). This number declines with age,stabilizing by adulthood. Estimates vary for an adult, ranging from 1014 to 5 x 1014 synapses (100to 500 trillion).

Mechanisms for propagating action potentials

In 1937, John Zachary Young suggested that the squid giant axon could be used to study neuronalelectrical properties. Being larger than but similar in nature to human neurons, squid cells were



easier to study. By inserting electrodes into the giant squid axons, accurate measurements weremade of the membrane potential.

The cell membrane of the axon and soma contain voltage-gated ion channels which allow theneuron to generate and propagate an electrical signal (an action potential). These signals aregenerated and propagated by charge-carrying ions including sodium (Na+), potassium (K+),chloride (Cl-), and calcium (Ca2+).

There are several stimuli that can activate a neuron leading to electrical activity, including pressure,stretch, chemical transmitters, and changes of the electric potential across the cell membrane.Stimuli cause specific ion-channels within the cell membrane to open, leading to a flow of ionsthrough the cell membrane, changing the membrane potential.

Thin neurons and axons require less metabolic expense to produce and carry action potentials, butthicker axons convey impulses more rapidly. To minimize metabolic expense while maintainingrapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheathsare formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in theperipheral nervous system. The sheath enables action potentials to travel faster than inunmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheralnerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodesof Ranvier which contain a high density of voltage-gated ion channels. Multiple sclerosis is aneurological disorder that results from demyelination of axons in the central nervous system.

Some neurons do not generate action potentials, but instead generate a graded electrical signal,which in turn causes graded neurotransmitter release. Such nonspiking neurons tend to be sensoryneurons or interneurons, because they cannot carry signals long distances.

Neural coding

Neural coding is concerned with how sensory and other information is represented in the brain byneurons. The main goal of studying neural coding is to characterize the relationship between thestimulus and the individual or ensemble neuronal responses, and the relationships amongst theelectrical activities of the neurons within the ensemble. It is thought that neurons can encode bothdigital and analog information.

All-or-none principle

The conduction of nerve impulses is an example of an all-or-none response. In other words, if aneuron responds at all, then it must respond completely. The greater the intensity of stimulationdoes not produce a stronger signal but can produce more impulses per second. There are differenttypes of receptor response to stimulus, slowly adapting or tonic receptors respond to steadystimulus and produce a steady rate of firing. These tonic receptors most often respond to increasedintensity of stimulus by increasing their firing frequency, usually as a power function of stimulusplotted against impulses per second. This can be likened to an intrinsic property of light where toget greater intensity of a specific frequency (color) there have to be more photons, as the photonscan't become "stronger" for a specific frequency.



There are a number of other receptor types that are called quickly-adapting or phasic receptors,where firing decreases or stops with steady stimulus; examples include: skin when touched by anobject causes the neurons to fire, but if the object maintains even pressure against the skin, theneurons stop firing. The neurons of the skin and muscles that are responsive to pressure andvibration have filtering accessory structures that aid their function. The pacinian corpuscle is onesuch structure; it has concentric layers like an onion which form around the axon terminal. Whenpressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon,which fires. If the pressure is steady, there is no more stimulus; thus, typically these neuronsrespond with a transient depolarization during the initial deformation and again when the pressureis removed, which causes the corpuscle to change shape again. Other types of adaptation areimportant in extending the function of a number of other neurons.

History

The term neuron was coined by the German anatomist Heinrich Wilhelm Waldeyer. The neuron'splace as the primary functional unit of the nervous system was first recognized in the early 20thcentury through the work of the Spanish anatomist Santiago Ramón y Cajal. Cajal proposed thatneurons were discrete cells that communicated with each other via specialized junctions, or spaces,between cells. This became known as the neuron doctrine, one of the central tenets of modernneuroscience. To observe the structure of individual neurons, Cajal used a silver staining methoddeveloped by his rival, Camillo Golgi. The Golgi stain is an extremely useful method forneuroanatomical investigations because, for reasons unknown, it stains a very small percentage ofcells in a tissue, so one is able to see the complete micro structure of individual neurons withoutmuch overlap from other cells in the densely packed brain.

The neuron doctrine

The neuron doctrine is the now fundamental idea that neurons are the basic structural andfunctional units of the nervous system. The theory was put forward by Santiago Ramón y Cajal inthe late 19th century. It held that neurons are discrete cells (not connected in a meshwork), acting asmetabolically distinct units.

Later discoveries yielded a few refinements to the simplest form of the doctrine. For example, glialcells, which are not considered neurons, play an essential role in information processing. Also,electrical synapses are more common than previously thought, meaning that there are direct,cytoplasmic connections between neurons. In fact, there are examples of neurons forming eventighter coupling: the squid giant axon arises from the fusion of multiple axons.

Cajal also postulated the Law of Dynamic Polarization, which states that a neuron receives signalsat its dendrites and cell body and transmits them, as action potentials, along the axon in onedirection: away from the cell body. The Law of Dynamic Polarization has important exceptions;dendrites can serve as synaptic output sites of neurons and axons can receive synaptic inputs

Neurons in the brain

The number of neurons in the brain varies dramatically from species to species. One estimate putsthe human brain at about 100 billion (1011) neurons and 100 trillion (1014) synapses. Anotherestimate is 86 billion neurons of which 16.3 billion are in the cerebral cortex and 69 billion in the



cerebellum. By contrast, the nematode worm Caenorhabditis elegans has just 302 neurons making itan ideal experimental subject as scientists have been able to map all of the organism's neurons. Thefruit fly Drosophila melanogaster, a common subject in biology experiments, has around 100,000neurons and exhibits many complex behaviors. Many properties of neurons, from the type ofneurotransmitters used to ion channel composition, are maintained across species, allowingscientists to study processes occurring in more complex organisms in much simpler experimentalsystems.

Neurological disorders

Charcot-Marie-Tooth disease (CMT), also known as Hereditary Motor and Sensory Neuropathy(HMSN), Hereditary Sensorimotor Neuropathy (HMSN), or Peroneal Muscular Atrophy, is aheterogeneous inherited disorder of nerves (neuropathy) that is characterized by loss of muscletissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in theadvanced stages of disease. Presently incurable, this disease is one of the most common inheritedneurological disorders, with 37 in 100,000 affected.

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative diseasecharacterized by progressive cognitive deterioration together with declining activities of dailyliving and neuropsychiatric symptoms or behavioral changes. The most striking early symptom isloss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomessteadily more pronounced with illness progression, with relative preservation of older memories.As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language(aphasia), skilled movements (apraxia), recognition (agnosia), and functions such as decision-making and planning get impaired.

Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of thecentral nervous system that often impairs the sufferer's motor skills and speech. Parkinson's diseasebelongs to a group of conditions called movement disorders. It is characterized by muscle rigidity,tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physicalmovement (akinesia). The primary symptoms are the results of decreased stimulation of the motorcortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine,which is produced in the dopaminergic neurons of the brain. Secondary symptoms may includehigh level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

Myasthenia Gravis is a neuromuscular disease leading to fluctuating muscle weakness andfatigability. Weakness is typically caused by circulating antibodies that block acetylcholinereceptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of theneurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants, cholinesteraseinhibitors and, in selected cases, thymectomy.

Demyelination

Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves.When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerveeventually withers. This leads to certain neurodegenerative disorders like multiple sclerosis, chronicinflammatory demyelinating polyneuropathy.



Axonal degeneration

Although most injury responses include a calcium influx signaling to promote resealing of severedparts, axonal injuries initially lead to acute axonal degeneration (AAD), which is rapid separationof the proximal and distal ends within 30 minutes of injury. Degeneration follows with swelling ofthe axolemma, and eventually leads to bead like formation. Granular disintegration of the axonalcytoskeleton and inner organelles occurs after axolemma degradation. Early changes includeaccumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulumdegrades and mitochondria swell up and eventually disintegrate. The disintegration is dependent onUbiquitin and Calpain proteases (caused by influx of calcium ion), suggesting that axonaldegeneration is an active process. Thus the axon undergoes complete fragmentation. The processtakes about roughly 24 hrs in the PNS, and longer in the CNS. The signaling pathways leading toaxolemma degeneration are currently unknown.

Nerve regeneration

It has been demonstrated that neurogenesis can sometimes occur in the adult vertebrate brain, and itis often possible for peripheral axons to regrow if they are severed. The latter can take a long time:after a nerve injury to the human arm, for example, it may take months for feeling to return to thehands and fingers.

Action potential (Nerve Impulses)

Action Potentials in neurons are also known as nerve impulses or spikes. In physiology, an actionpotential is a short-lasting event in which the electrical membrane potential of a cell rapidly risesand falls, following a stereotyped trajectory. Action potentials occur in several types of animalcells, called excitable cells, which include neurons, muscle cells, and endocrine cells. In neurons,they play a central role in cell-to-cell communication. In other types of cells, their main function isto activate intracellular processes. In muscle cells, for example, an action potential is the first stepin the chain of events leading to contraction. In beta cells of the pancreas, they provoke release ofinsulin. Action potentials in neurons are also known as "nerve impulses" or "spikes", and thetemporal sequence of action potentials generated by a neuron is called its "spike train". A neuronthat emits an action potential is often said to "fire".

Action potentials are generated by special types of voltage-gated ion channels embedded in a cell'splasma membrane. These channels are shut when the membrane potential is near the restingpotential of the cell, but they rapidly begin to open if the membrane potential increases to aprecisely defined threshold value. When the channels open, they allow an inward flow of sodiumions, which changes the electrochemical gradient, which in turn produces a further rise in themembrane potential. This then causes more channels to open, producing a greater electrical current,and so on. The process proceeds explosively until all of the available ion channels are open,resulting in a large upswing in the membrane potential. The rapid influx of sodium ions causes thepolarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As thesodium channels close, sodium ions can no longer enter the neuron, and they are activelytransported out the plasma membrane. Potassium channels are then activated, and there is anoutward current of potassium ions, returning the electrochemical gradient to the resting state. Afteran action potential has occurred, there is a transient negative shift, called the afterhyperpolarization



or refractory period, due to additional potassium currents. This is the mechanism which prevents anaction potential traveling back the way it just came.

In animal cells, there are two primary types of action potentials, one type generated by voltage-gated sodium channels, the other by voltage-gated calcium channels. Sodium-based actionpotentials usually last for less than one millisecond, whereas calcium-based action potentials maylast for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide thedriving force for a long burst of rapidly-emitted sodium spikes. In cardiac muscle cells, on the otherhand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike,which then produces muscle contraction.

Overview for a typical neuron

All cells in animal body tissues are electrically polarized—in other words, they maintain a voltagedifference across the cell's plasma membrane, known as the membrane potential. This electricalpolarization results from a complex interplay between protein structures embedded in themembrane called ion pumps and ion channels. In neurons, the types of ion channels in themembrane usually vary across different parts of the cell, giving the dendrites, axon, and cell bodydifferent electrical properties. As a result, some parts of the membrane of a neuron may beexcitable (capable of generating action potentials) while others are not. The most excitable part of aneuron is usually the axon hillock (the point where the axon leaves the cell body), but the axon andcell body are also excitable in most cases.

Each excitable patch of membrane has two important levels of membrane potential: the restingpotential, which is the value the membrane potential maintains as long as nothing perturbs the cell,and a higher value called the threshold potential. At the axon hillock of a typical neuron, the restingpotential is around -70 millivolts (mV) and the threshold potential is around -55 mV. Synapticinputs to a neuron cause the membrane to depolarize or hyperpolarize; that is, they cause themembrane potential to rise or fall. Action potentials are triggered when enough depolarizationaccumulates to bring the membrane potential up to threshold. When an action potential is triggered,the membrane potential abruptly shoots upward, often reaching as high as +100 mV, then equallyabruptly shoots back downward, often ending below the resting level, where it remains for someperiod of time. The shape of the action potential is stereotyped; that is, the rise and fall usually haveapproximately the same amplitude and time course for all action potentials in a given cell.(Exceptions are discussed later in the article.) In most neurons, the entire process takes place in lessthan a thousandth of a second. Many types of neurons emit action potentials constantly at rates ofup to 10-100 per second; some types, however, are much quieter, and may go for minutes or longerwithout emitting any action potentials.

At the biophysical level, action potentials result from special types of voltage-gated ion channels.As the membrane potential is increased, sodium ion channels open, allowing the entry of sodiumions into the cell. This is followed by the opening of potassium ion channels that permit the exit ofpotassium ions from the cell. The inward flow of sodium ions increases the concentration ofpositively-charged cations in the cell and causes depolarization, where the potential of the cell ishigher than the cell's resting potential. The sodium channels close at the peak of the actionpotential, while potassium continues to leave the cell. The efflux of potassium ions decreases themembrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassiumcurrent exceeds the sodium current and the voltage returns to its normal resting value, typically 70



mV. However, if the voltage increases past a critical threshold, typically 15 mV higher than theresting value, the sodium current dominates. This results in a runaway condition whereby thepositive feedback from the sodium current activates even more sodium channels. Thus, the cell"fires," producing an action potential.

Currents produced by the opening of voltage-gated channels in the course of an action potential aretypically significantly larger than the initial stimulating current. Thus the amplitude, duration, andshape of the action potential are largely determined by the properties of the excitable membraneand not the amplitude or duration of the stimulus. This all-or-nothing property of the actionpotential sets it apart from graded potentials such as receptor potentials, electrotonic potentials, andsynaptic potentials, which scale with the magnitude of the stimulus. A variety of action potentialtypes exist in many cell types and cell compartments as determined by the types of voltage-gatedchannels, leak channels, channel distributions, ionic concentrations, membrane capacitance,temperature, and other factors.

The principal ions involved in an action potential are sodium and potassium cations; sodium ionsenter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross themembrane for the membrane voltage to change drastically. The ions exchanged during an actionpotential, therefore, make a negligible change in the interior and exterior ionic concentrations. Thefew ions that do cross are pumped out again by the continual action of the sodium–potassiumpump, which, with other ion transporters, maintains the normal ratio of ion concentrations acrossthe membrane. Calcium cations and chloride anions are involved in a few types of action potentials,such as the cardiac action potential and the action potential in the single-celled alga Acetabularia,respectively.

Although action potentials are generated locally on patches of excitable membrane, the resultingcurrents can trigger action potentials on neighboring stretches of membrane, precipitating adomino-like propagation. In contrast to passive spread of electric potentials (electrotonic potential),action potentials are generated anew along excitable stretches of membrane and propagate withoutdecay.Myelinated sections of axons are not excitable and do not produce action potentials and thesignal is propagated passively as electrotonic potential. Regularly spaced unmyelinated patches,called the nodes of Ranvier, generate action potentials to boost the signal. Known as saltatoryconduction, this type of signal propagation provides a favorable tradeoff of signal velocity and axondiameter. Depolarization of axon terminals, in general, triggers the release of neurotransmitter intothe synaptic cleft. In addition, backpropagating action potentials have been recorded in thedendrites of pyramidal neurons, which are ubiquitous in the neocortex. These are thought to have arole in spike-timing-dependent plasticity.

Biophysical and cellular context

Electrical signals within biological organisms are, in general, driven by ions. The most importantcations for the action potential are sodium (Na+) and potassium (K+). Both of these are monovalentcations that carry a single positive charge. Action potentials can also involve calcium (Ca2+),which is a divalent cation that carries a double positive charge. The chloride anion (Cl−) plays amajor role in the action potentials of some algae, but plays a negligible role in the action potentialsof most animals.



Ions cross the cell membrane under two influences: diffusion and electric fields. A simple examplewherein two solutions - A and B - are separated by a porous barrier illustrates that diffusion willensure that they will eventually mix into equal solutions. This mixing occurs because of thedifference in their concentrations. The region with high concentration will diffuse out toward theregion with low concentration. To extend the example, let solution A have 30 sodium ions and 30chloride ions. Also, let solution B have only 20 sodium ions and 20 chloride ions. Assuming thebarrier allows both types of ions to travel through it, then a steady state will be reached wherebyboth solutions have 25 sodium ions and 25 chloride ions. If, however, the porous barrier is selectiveto which ions are let through, then diffusion alone will not determine the resulting solution.Returning to the previous example, let's now construct a barrier that is permeable only to sodiumions. Since solution B has a lower concentration of both sodium and chloride, the barrier will attractboth ions from solution A. However, only sodium will travel through the barrier. This will result inan accumulation of sodium in solution B. Since sodium has a positive charge, this accumulationwill make solution B more positive relative to solution A. Positive sodium ions will be less likely totravel to the now-more-positive B solution. This constitutes the second factor controlling ion flow,namely electric fields. The point at which this electric field completely counteracts the force due todiffusion is called the equilibrium potential. At this point, the net flow of this specific ion (in thiscase sodium) is zero.

Cell membrane

Each neuron is encased in a cell membrane, made of a phospholipid bilayer. This membrane isnearly impermeable to ions. To transfer ions into and out of the neuron, the membrane provides twostructures. Ion pumps use the cell's energy to continuously move ions in and out. They createconcentration differences (between the inside and outside of the neuron) by transporting ionsagainst their concentration gradients (from regions of low concentration to regions of highconcentration). The ion channels then use this concentration difference to transport ions down theirconcentration gradients (from regions of high concentration to regions of low concentration).However, unlike the continuous transport by the ion pumps, the transport by the ion channels isnoncontinuous. They open and close in response to signals only from their environment. Thistransport of ions through the ion channels then changes the voltage of the cell membrane. Thesechanges are what bring about an action potential. As an analogy, ion pumps play the role of thebattery that allows a radio circuit (the ion channels) to transmit a signal (action potential).

Membrane potential

The cell membrane acts as a barrier that prevents the inside solution (intracellular fluid) frommixing with the outside solution (extracellular fluid). These two solutions have differentconcentrations of their ions. Furthermore, this difference in concentrations leads to a difference incharge of the solutions. This creates a situation whereby one solution is more positive than theother. Therefore, positive ions will tend to gravitate towards the negative solution. Likewise,negative ions will tend to gravitate towards the positive solution. To quantify this property, onewould like to somehow capture this relative positivity (or negativity). To do this, the outsidesolution is set as the zero voltage. Then the difference between the inside voltage and the zerovoltage is determined. For example, if the outside voltage is 100 mV, and the inside voltage is 30mV, then the difference is 70 mV. This difference is what is commonly referred to as the membranepotential.



Ion channels

Ion channels are integral membrane proteins with a pore through which ions can travel betweenextracellular space and cell interior. Most channels are specific (selective) for one ion; for example,most potassium channels are characterized by 1000:1 selectivity ratio for potassium over sodium,though potassium and sodium ions have the same charge and differ only slightly in their radius. Thechannel pore is typically so small that ions must pass through it in single-file order. Channel porecan be either open or closed for ion passage, although a number of channels demonstrate varioussub-conductance levels. When a channel is open, ions permeate through the channel pore down thetransmembrane concentration gradient for that particular ion. Rate of ionic flow through thechannel, i.e. single-channel current amplitude, is determined by the maximum channel conductanceand electrochemical driving force for that ion, which is the difference between instantaneous valueof the membrane potential and the value of the reversal potential.

A channel may have several different states (corresponding to different conformations of theprotein), but each such state is either open or closed. In general, closed states correspond either to acontraction of the pore — making it impassable to the ion — or to a separate part of the protein,stoppering the pore. For example, the voltage-dependent sodium channel undergoes inactivation, inwhich a portion of the protein swings into the pore, sealing it. This inactivation shuts off thesodium current and plays a critical role in the action potential.

Ion channels can be classified by how they respond to their environment. For example, the ionchannels involved in the action potential are voltage-sensitive channels; they open and close inresponse to the voltage across the membrane. Ligand-gated channels form another important class;these ion channels open and close in response to the binding of a ligand molecule, such as aneurotransmitter. Other ion channels open and close with mechanical forces. Still other ionchannels—such as those of sensory neurons—open and close in response to other stimuli, such aslight, temperature or pressure.

Ion pumps

The ionic currents of the action potential flow in response to concentration differences of the ionsacross the cell membrane. These concentration differences are established by ion pumps, which areintegral membrane proteins that carry out active transport, i.e., use cellular energy (ATP) to "pump"the ions against their concentration gradient. Such ion pumps take in ions from one side of themembrane (decreasing its concentration there) and release them on the other side (increasing itsconcentration there). The ion pump most relevant to the action potential is the sodium–potassiumpump, which transports three sodium ions out of the cell and two potassium ions in. As aconsequence, the concentration of potassium ions K+ inside the neuron is roughly 20-fold largerthan the outside concentration, whereas the sodium concentration outside is roughly ninefold largerthan inside. In a similar manner, other ions have different concentrations inside and outside theneuron, such as calcium, chloride and magnesium.

Ion pumps influence the action potential only by establishing the relative ratio of intracellular andextracellular ion concentrations. The action potential involves mainly the opening and closing ofion channels, not ion pumps. If the ion pumps are turned off by removing their energy source, or byadding an inhibitor such as ouabain, the axon can still fire hundreds of thousands of action



potentials before their amplitudes begin to decay significantly. In particular, ion pumps play nosignificant role in the repolarization of the membrane after an action potential.

Resting potential

As described in the section Ions and the forces driving their motion, equilibrium or reversalpotential of an ion is the value of transmembrane voltage at which the electric force generated bydiffusional movement of the ion down its concentration gradient becomes equal to the molecularforce of that diffusion. The equilibrium potential for any ion can be calculated using the Nernstequation.Generation of resting membrane potential is explicitly explained by the Goldman equation. Theresting plasma membrane of most animal cells is much more permeable to K+, which results in theresting potential Vrest to be close to the potassium equilibrium potential.

It is important to realize that ionic and water permeability of a pure lipid bilayer is very small, andit is, in a similar manner, negligible for ions of comparable size, such as Na+ and K+. The cellmembranes, however, contain a large number of ion channels, water channels (aquaporins), andvarious ionic pumps, exchangers, and transporters, which dramatically and selectively increasepermeability of the membrane for different ions. The relatively high membrane permeability forpotassium ions at resting potential results from Inward-rectifier potassium ion channels, which areopen at negative voltages, and so-called leak potassium conductances such as open rectifier K+channel (ORK+), which are locked in open state. These potassium channels should not be confusedwith voltage-activated K+ channels responsible for membrane repolarization during actionpotential.

A depiction of two neurons where the first upper right neuron is connected through extensions ofthe cell surface of the neuron known as dendrites to the second lower left neuron. The main body ofthe neuron is approximately spherical in shape where the dendrites resemble tree branches thatextend from the central body (or "tree trunk") of the neuron. An action potential from the centralbody of the first cell travels along the surface of its dendrites toward the second cell. A blowupinsert in the figure shows the connection between the dendrite of the first cell to the surface of thesecond cell. The end of the dendrite contains neurotransmitters stored in vesicles. Theseneurotransmitters are released from the dendrites by an action potential. The neurotransmitters thendiffuse through the solution between the two cells where they bind to cell surface receptors on thesecond cell.

Anatomy of a neuron

Several types of cells support an action potential, such as plant cells, muscle cells, and thespecialized cells of the heart (in which occurs the cardiac action potential). However, the mainexcitable cell is the neuron, which also has the simplest mechanism for the action potential.

Neurons are electrically excitable cells composed, in general, of one or more dendrites, a singlesoma, a single axon and one or more axon terminals. The dendrite is one of the two types ofsynapses, the other being the axon terminal boutons. Dendrites form protrusions in response to theaxon terminal boutons. These protrusions, or spines, are designed to capture the neurotransmittersreleased by the presynaptic neuron. They have a high concentration of ligand activated channels. Itis, therefore, here where synapses from two neurons communicate with one another. These spines



have a thin neck connecting a bulbous protrusion to the main dendrite. This ensures that changesoccurring inside the spine are less likely to affect the neighbouring spines. The dendritic spine can,therefore, with rare exception (see LTP), act as an independent unit. The dendrites then connectonto the soma. The soma houses the nucleus, which acts as the regulator for the neuron. Unlike thespines, the surface of the soma is populated by voltage activated ion channels. These channels helptransmit the signals generated by the dendrites. Emerging out from the soma is the axon hillock.This region is characterized by having an incredibly high concentration of voltage activated sodiumchannels. In general, it is considered to be the spike initiation zone for action potentials. Multiplesignals generated at the spines, and transmitted by the soma all converge here. Immediately afterthe axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. Theaxon is insulated by a myelin sheath. Myelin is composed of Schwann cells that wrap themselvesmultiple times around the axonal segment. This forms a thick fatty layer that prevents ions fromentering or escaping the axon. This insulation both prevents significant signal decay as well asensuring faster signal speed. This insulation, however, has the restriction that no channels can bepresent on the surface of the axon. There are, therefore, regularly spaced patches of membrane,which have no insulation. These nodes of ranvier can be considered to be 'mini axon hillocks' astheir purpose is to boost the signal in order to prevent significant signal decay. At the furthest end,the axon loses its insulation and begins to branch into several axon terminals. These axon terminalsthen end in the form the second class of synapses, axon terminal buttons. These buttons havevoltage-activated calcium channels, which come into play when signaling other neurons.

Initiation

Before considering the propagation of action potentials along axons and their termination at thesynaptic knobs, it is helpful to consider the methods by which action potentials can be initiated atthe axon hillock. The basic requirement is that the membrane voltage at the hillock be raised abovethe threshold for firing. There are several ways in which this depolarization can occur.The pre- and post-synaptic axons are separated by a short distance known as the synaptic cleft.Neurotransmitter released by pre-synaptic axons diffuse through the synaptic clef to bind to andopen ion channels in post-synaptic axons.

When an action potential arrives at the end of the pre-synaptic axon (yellow), it causes the releaseof neurotransmitter molecules that open ion channels in the post-synaptic neuron (green). Thecombined excitatory and inhibitory postsynaptic potentials of such inputs can begin a new actionpotential in the post-synaptic neuron.

Each action potential is followed by a refractory period, which can be divided into an absoluterefractory period, during which it is impossible to evoke another action potential, and then arelative refractory period, during which a stronger-than-usual stimulus is required. These tworefractory periods are caused by changes in the state of sodium and potassium channel molecules.When closing after an action potential, sodium channels enter an "inactivated" state, in which theycannot be made to open regardless of the membrane potential—this gives rise to the absoluterefractory period. Even after a sufficient number of sodium channels have transitioned back to theirresting state, it frequently happens that a fraction of potassium channels remains open, making itdifficult for the membrane potential to depolarize, and thereby giving rise to the relative refractoryperiod. Because the density and subtypes of potassium channels may differ greatly betweendifferent types of neurons, the duration of the relative refractory period is highly variable.



The absolute refractory period is largely responsible for the unidirectional propagation of actionpotentials along axons. At any given moment, the patch of axon behind the actively spiking part isrefractory, but the patch in front, not having been activated recently, is capable of being stimulatedby the depolarization from the action potential.

Propagation

The action potential generated at the axon hillock propagates as a wave along the axon. Thecurrents flowing inwards at a point on the axon during an action potential spread out along theaxon, and depolarize the adjacent sections of its membrane. If sufficiently strong, thisdepolarization provokes a similar action potential at the neighboring membrane patches. This basicmechanism was demonstrated by Alan Lloyd Hodgkin in 1937. After crushing or cooling nervesegments and thus blocking the action potentials, he showed that an action potential arriving on oneside of the block could provoke another action potential on the other, provided that the blockedsegment was sufficiently short.

Once an action potential has occurred at a patch of membrane, the membrane patch needs time torecover before it can fire again. At the molecular level, this absolute refractory period correspondsto the time required for the voltage-activated sodium channels to recover from inactivation, i.e., toreturn to their closed state. There are many types of voltage-activated potassium channels inneurons, some of them inactivate fast (A-type currents) and some of them inactivate slowly or notinactivate at all; this variability guarantees that there will be always an available source of currentfor repolarization, even if some of the potassium channels are inactivated because of precedingdepolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate withinseveral millisecond during strong depolarization, thus making following depolarization impossibleuntil a substantial fraction of sodium channels is not returned to their closed state. Although itlimits the frequency of firing, the absolute refractory period ensures that the action potential movesin only one direction along an axon. The currents flowing in due to an action potential spread out inboth directions along the axon. However, only the unfired part of the axon can respond with anaction potential; the part that has just fired is unresponsive until the action potential is safely out ofrange and cannot restimulate that part. In the usual orthodromic conduction, the action potentialpropagates from the axon hillock towards the synaptic knobs (the axonal termini); propagation inthe opposite direction—known as antidromic conduction—is very rare. However, if a laboratoryaxon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired; then two actionpotentials will be generated, one traveling towards the axon hillock and the other traveling towardsthe synaptic knobs.

Axons of neurons are wrapped by several myelin sheaths, which shield the axon from extracellularfluid. There are short gaps between the myelin sheaths known as nodes of Ranvier where the axonis directly exposed to the surrounding extracellular fluid.

In saltatory conduction, an action potential at one node of Ranvier causes inwards currents thatdepolarize the membrane at the next node, provoking a new action potential there; the actionpotential appears to "hop" from node to node.



Myelin and saltatory conduction

The evolutionary need for the fast and efficient transduction of electrical signals in nervous systemresulted in appearance of myelin sheaths around neuronal axons. Myelin is a multilamellarmembrane that enwraps the axon in segments separated by intervals known as nodes of Ranvier, isproduced by specialized cells, Schwann cells exclusively in the peripheral nervous system, and byoligodendrocytes exclusively in the central nervous system. Myelin sheath reduces membranecapacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast,saltatory movement of action potentials from node to node. Myelination is found mainly invertebrates, but an analogous system has been discovered in a few invertebrates, such as somespecies of shrimp. Not all neurons in vertebrates are myelinated; for example, axons of the neuronscomprising autonomous (vegetative) nervous system are not myelinated in general.

Myelin prevents ions from entering or leaving the axon along myelinated segments. As a generalrule, myelination increases the conduction velocity of action potentials and makes them moreenergy-efficient. Whether saltatory or not, the mean conduction velocity of an action potentialranges from 1 m/s to over 100 m/s, and, in general, increases with axonal diameter.

Action potentials cannot propagate through the membrane in myelinated segments of the axon.However, the current is carried by the cytoplasm, which is sufficient to depolarize the next 1 or 2node of Ranvier. Instead, the ionic current from an action potential at one node of Ranvier provokesanother action potential at the next node; this apparent "hopping" of the action potential from nodeto node is known as saltatory conduction.

Myelin has two important advantages: fast conduction speed and energy efficiency. For axonslarger than a minimum diameter (roughly 1 micrometre), myelination increases the conductionvelocity of an action potential, typically tenfold. Conversely, for a given conduction velocity,myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentialsmove at roughly the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squidgiant axon, but the frog axon has a roughly 30-fold smaller diameter and 1000-fold smaller cross-sectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer ions"leak" across the membrane, saving metabolic energy. This saving is a significant selectiveadvantage, since the human nervous system uses approximately 20% of the body's metabolicenergy.

The length of axons' myelinated segments is important to the success of saltatory conduction. Theyshould be as long as possible to maximize the speed of conduction, but not so long that the arrivingsignal is too weak to provoke an action potential at the next node of Ranvier. In nature, myelinatedsegments are generally long enough for the passively propagated signal to travel for at least twonodes while retaining enough amplitude to fire an action potential at the second or third node. Thus,the safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case ofinjury. However, action potentials may end prematurely in certain places where the safety factor islow, even in unmyelinated neurons; a common example is the branch point of an axon, where itdivides into two axons.

Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity ofaction potentials. The most well-known of these is multiple sclerosis, in which the breakdown ofmyelin impairs coordinated movement.



Termination

Chemical synapses

In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be releasedinto the synaptic cleft. Neurotransmitters are small molecules that may open ion channels in thepostsynaptic cell; most axons have the same neurotransmitter at all of their termini. The arrival ofthe action potential opens voltage-sensitive calcium channels in the presynaptic membrane; theinflux of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface andrelease their contents into the synaptic cleft. This complex process is inhibited by the neurotoxinstetanospasmin and botulinum toxin, which are responsible for tetanus and botulism, respectively.Electrical synapases are composed of protein complexes that are imbedded in both membranes ofadjacent neurons and thereby provide a direct channel for ions to flow from the cytoplasm of onecell into an adjacent cell.

Electrical synapses between excitable cells allow ions to pass directly from one cell to another, andare much faster than chemical synapses.

Electrical synapses

Some synapses dispense with the "middleman" of the neurotransmitter, and connect the presynapticand postsynaptic cells together.

When an action potential reaches such a synapse, the ionic currents flowing into the presynapticcell can cross the barrier of the two cell membranes and enter the postsynaptic cell through poresknown as connexins.

Thus, the ionic currents of the presynaptic action potential can directly stimulate the postsynapticcell. Electrical synapses allow for faster transmission because they do not require the slow diffusionof neurotransmitters across the synaptic cleft. Hence, electrical synapses are used whenever fastresponse and coordination of timing are crucial, as in escape reflexes, the retina of vertebrates, andthe heart.

Neuromuscular junctions

A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motorneuron terminates on a muscle fiber. In such cases, the released neurotransmitter is acetylcholine,which binds to the acetylcholine receptor, an integral membrane protein in the membrane (thesarcolemma) of the muscle fiber. However, the acetylcholine does not remain bound; rather, itdissociates and is hydrolyzed by the enzyme, acetylcholinesterase, located in the synapse. Thisenzyme quickly reduces the stimulus to the muscle, which allows the degree and timing ofmuscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase toprevent this control, such as the nerve agents sarin and tabun, and the insecticides diazinon andmalathion.



Method and device for evaluating nerve impulse propagation velocity and latency ofelectrodermal reflexes

The method and reactometric device provide for separate or simultaneous evaluation of latency andelectrodermal reflex propagation speed through postganglionic sympathetic nerve fibers.Evaluation is carried out by help of electronic interval counting devices and yields certaincorrelations enabling differentiation between the central and peripheral neurovegetative fatigue aswell as intoxication phenomena of peripheral vegetative fibers. Evaluations are conducted throughtwo electrodes located on the same innervation area, i.e. on the longitudinal axis of palm, theelectrodes being spaced by a known distance which is considered in the evaluation of electrodermalreflex propagation. The first electrode intercepts the electrodermal reflex used in the evaluation oflatency.

Electrical processes involved in the encoding of nerve impulses.

A mechanism for impulse encoding is advanced for those neurones whose impulse trigger zonemembrane is more excitable than the general axonal membrane. Electrical communication betweenan electrotonically small patch of highly excitable membrane and neighboring membrane places thecontrol of membrane potential - in varying degree - to the larger membrane area throughout theinterspike intervals. That control is relinquished to the trigger membrane near the time of actionpotential initiation in a natural fashion. Model calculations demonstrate that this mechanism canlead to a dramatic lowering of the minimum stable firing frequency of tonic neurons, and,additionally influence the shape of the stimulus - versus - impulse frequency curve. The results arecompared with the behavior of the slowly adapting stretch receptor neuron of the crayfish.

All-or-none law

The all-or-none law is the principle that the strength by which a nerve or muscle fiber responds toa stimulus is not dependent on the strength of the stimulus. If the stimulus is any strength abovethreshold, the nerve or muscle fiber will give a complete response or otherwise no response at all.

It was first established by the American physiologist Henry Pickering Bowditch in 1871 for thecontraction of heart muscle. According to him, describing the relation of response to stimulus,

“An induction shock produces a contraction or fails to do so according to its strength; if it does soat all, it produces the greatest contraction that can be produced by any strength of stimulus in thecondition of the muscle at the time.”

The individual fibers of both skeletal muscle and nerve respond to stimulation according to the all-or-none principle.

Relationship between stimulus and response

The magnitude of the spike potential set up in any single nerve fiber is independent of the strengthof the exciting stimulus, provided the latter is adequate. An electrical stimulus below thresholdstrength fails to elicit a propagated spike potential. If it is of threshold strength or over, a spike(representing a nervous impulse) of maximum magnitude is set up. Either the single fiber does notrespond with spike production, or it responds to the utmost of its ability under the conditions at the



moment. This property of the single nerve fiber is termed the all-or-none relationship. It should beemphasized relationship applies only to the unit of tissue, as well as to skeletal muscle units (theunit being the individual muscle fiber) and to the heart(the unit being the entire auricles or theentire ventricles).

Stimuli too weak to produce a spike do, however, set up a local electrotonus, the magnitude of theelectronic potential progressively increasing with the strength of the stimulus, until a spike isgenerated.cellular reproduction is when a a neuron sends electro chemical waves down the spinalcord This demonstrates the all-or-none relationship in spike production.

The above account deals with the response of a single nerve fiber. If a nerve trunk is stimulated,then as the exciting stimulus is progressively increased above threshold, a larger number of fibersrespond. The minimal effective (i.e. threshold) stimulus is adequate only for fibers of highexcitability, but a stronger stimulus excites all the nerve fibers. Increasing the stimulus further doesincrease the response of whole nerve.

Heart muscle is excitable, i.e. it responds to external stimuli by contracting. If the external stimulusis too weak, no response is obtained; if the stimulus is adequate, the heart responds to the best of itsability. Accordingly, the auricles or ventricles behave as a single unit, so that an adequate stimulusnormally produces a full contraction of either the auricles or ventricles. The force of the contractionobtained depends on the state in which the muscles fibers find themselves. In the case of musclefibers, the individual muscle fiber does not respond at all if the stimulus is too weak. However, itresponds maximally when the stimulus rises to threshold. The contraction is not increased if thestimulus strength is further raise. Stronger stimuli bring more muscle fibers into action and thus thetension of a muscle increases as the strength of the stimulus applied to it rises.

Resting potential- Chemical Characteristics

The relatively static membrane potential of quiescent cells is called the resting membranepotential (or resting voltage), as opposed to the specific dynamic electrochemical phenomenonacalled action potential and graded membrane potential.

Apart from the latter two, which occur in excitable cells (neurons, muscles, and some secretorycells in glands), membrane voltage in the majority of not-excitable cells can also undergo changesin response to environmental or intracellular stimuli [citation needed]. In principle, there is no differencebetween resting membrane potential and dynamic voltage changes like action potential frombiophysical point of view: all these phenomena are caused by specific changes in membranepermeabilities for potassium, sodium, calcium, and chloride, which in turn result from concertedchanges in functional activity of various ion channels, ion transporters, and exchangers.Conventionally, resting membrane potential can be defined as a relatively stable, ground value oftransmembrane voltage in animal and plant cells.

Any voltage is a difference in electric potential between two points - for example, the separation ofpositive and negative electric charges on opposite sides of a resistive barrier. The typical restingmembrane potential of a cell arises from the separation of potassium ions from intracellular,relatively immobile anions across the membrane of the cell. Because the membrane permeabilityfor potassium is much higher than that for other ions (disregarding voltage-gated channels at this



stage), and because of the strong chemical gradient for potassium, potassium ions flow from thecytosol into the extracellular space carrying out positive charge, until their movement is balancedby build-up of negative charge on the inner surface of the membrane. Again, because of the highrelative permeability for potassium, the resulting membrane potential is almost always close to thepotassium reversal potential. But in order for this process to occur, a concentration gradient ofpotassium ions must first be set up. This work is done by the ion pumps/transporters and/orexchangers and generally is powered by ATP.

In the case of the resting membrane potential across an animal cell's plasma membrane, potassium(and sodium) gradients are established by the Na+/K+-ATPase (sodium-potassium pump) whichtransports 2 potassium ions inside and 3 sodium ions outside at the cost of 1 ATP molecule. Inother cases, for example, a membrane potential may be established by acidification of the inside ofa membranous compartment (such as the proton pump that generates membrane potential acrosssynaptic vesicle membranes).

Electroneutrality

In most quantitative treatments of membrane potential, such as the derivation of Goldman equation,electroneutrality is assumed; that is, that there is no measurable charge excess in any side of themembrane. So, although there is an electric potential across the membrane due to charge separation,there is no actual measurable difference in the global concentration of positive and negative ionsacross the membrane (as it is estimated below), that is, there is no actual measurable charge excessin either side. That occurs because the effect of charge on electrochemical potential is hugelygreater than the effect of concentration so an undetectable change in concentration creates a greatchange on electric potential.

Generation of the resting potential

Cell membranes are typically permeable to only a subset of ionic species. These species usuallyinclude potassium ions, chloride ions, bicarbonate ions, and others. To simplify the description ofthe ionic basis of the resting membrane potential, it is most useful to consider only one ionicspecies at first, and consider the others later. Since trans-plasma-membrane potentials are almostalways determined primarily by potassium permeability, that is where to start.

The resting voltage is the result of several ion-translocating enzymes (uniporters, cotransporters,and pumps) in the plasma membrane, steadily operating in parallel, whereby each ion-translocatorhas its characteristic electromotive force (= reversal potential = 'equilibrium voltage'), depending onthe particular substrate concentrations inside and outside (internal ATP included in case of somepumps). H+ exporting ATPase render the membrane voltage in plants and fungi much morenegative than in the more extensively investigated animal cells, where the resting voltage is mainlydetermined by selective ion channels.

In most neurons the resting potential has a value of approximately -70 mV. The resting potential ismostly determined by the concentrations of the ions in the fluids on both sides of the cell membraneand the ion transport proteins that are in the cell membrane. How the concentrations of ions and themembrane transport proteins influence the value of the resting potential is outlined below.



The resting potential of a cell can be most thoroughly understood by thinking of it in terms ofequilibrium potentials. In the example diagram here, the model cell was given only one permeantion (potassium). In this case, the resting potential of this cell would be the same as the equilibriumpotential for potassium.

However, a real cell is more complicated, having permeabilities to many ions, each of whichcontributes to the resting potential. To understand better, consider a cell with only two permeantions, potassium and sodium. Consider a case where these two ions have equal concentrationgradients directed in opposite directions, and that the membrane permeabilities to both ions areequal. K+ leaving the cell will tend to drag the membrane potential toward EK. Na+ entering the cellwill tend to drag the membrane potential toward the reversal potential for sodium ENa. Since thepermeabilities to both ions were set to be equal, the membrane potential will, at the end of theNa+/K+ tug-of-war, end up halfway between ENa and EK. As ENa and EK were equal but of oppositesigns, halfway in between is zero, meaning that the membrane will rest at 0 mV.

Note that even though the membrane potential at 0 mV is stable, it is not an equilibrium conditionbecause neither of the contributing ions are in equilibrium. Ions diffuse down their electrochemicalgradients through ion channels, but the membrane potential is upheld by continual K+ influx andNa+ efflux via ion transporters. Such situation with similar permeabilities for counter-acting ions,like potassium and sodium in animal cells, can be extremely costly for the cell if thesepermeabilities are relatively large, as it takes a lot of ATP energy to pump the ions back. Becauseno real cell can afford such equal and large ionic permeabilities at rest, resting potential of animalcells is determined by predominant high permeability to potassium and adjusted to the requiredvalue by modulating sodium and chloride permeabilities and gradients.

In a healthy animal cell Na+ permeability is about 5% of the K permeability or even less,whereas the respective reversal potentials are +60 mV for sodium (ENa)and -80 mV forpotassium (EK). Thus the membrane potential will not be right at EK, but rather depolarizedfrom EK by an amount of approximately 5% of the 140 mV difference

Membrane transport proteins

For determination of membrane potentials, the two most important types of membrane ion transportproteins are ion channels and ion transporters. Ion channel proteins create paths across cellmembranes through which ions can passively diffuse without direct expenditure of metabolicenergy. They have selectivity for certain ions, thus, there are potassium-, chloride-, and sodium-selective ion channels. Different cells and even different parts of one cell (dendrites, cell bodies,nodes of Ranvier) will have different amounts of various ion transport proteins. Typically, theamount of certain potassium channels is most important for control of the resting potential (seebelow). Some ion pumps such as the Na+/K+-ATPase are electrogenic, that is, they produce chargeimbalance across the cell membrane and can also contribute directly to the membrane potential.Most pumps use metabolic energy (ATP) to function.

Equilibrium potentials

For most animal cells potassium ions (K+) are the most important for the resting potential. Due tothe active transport of potassium ions, the concentration of potassium is higher inside cells thanoutside. Most cells have potassium-selective ion channel proteins that remain open all the time.



There will be net movement of positively-charged potassium ions through these potassium channelswith a resulting accumulation of excess negative charge inside of the cell. The outward movementof positively-charged potassium ions is due to random molecular motion (diffusion) and continuesuntil enough excess negative charge accumulates inside the cell to form a membrane potentialwhich can balance the difference in concentration of potassium between inside and outside the cell."Balance" means that the electrical force (potential) that results from the build-up of ionic charge,and which impedes outward diffusion, increases until it is equal in magnitude but opposite indirection to the tendency for outward diffusive movement of potassium. This balance point is anequilibrium potential as the net transmembrane flux (or current) of K+ is zero. The equilibriumpotential for a given ion depends only upon the concentrations on either side of the membrane andthe temperature. It can be calculated using the Nernst equation.

Potassium equilibrium potentials of around -80 millivolts (inside negative) are common.Differences are observed in different species, different tissues within the same animal, and the sametissues under different environmental conditions. Applying the Nernst Equation above, one mayaccount for these differences by changes in relative K+ concentration or differences in temperature.

Resting potentials

The resting membrane potential is not an equilibrium potential as it relies on the constantexpenditure of energy (for ionic pumps as mentioned above) for its maintenance. It is a dynamicdiffusion potential that takes mechanism into account—wholly unlike the equilibrium potential,which is true no matter the nature of the system under consideration. The resting membranepotential is dominated by the ionic species in the system that has the greatest conductance acrossthe membrane. For most cells this is potassium. As potassium is also the ion with the most negativeequilibrium potential, usually the resting potential can be no more negative than the potassiumequilibrium potential. The resting potential can be calculated with the Goldman-Hodgkin-Katzvoltage equation using the concentrations of ions as for the equilibrium potential while alsoincluding the relative permeabilities, or conductances, of each ionic species. Under normalconditions, it is safe to assume that only potassium, sodium (Na+) and chloride (Cl-) ions play largeroles for the resting potential.

Measuring resting potentials

In some cells, the membrane potential is always changing (such as cardiac pacemaker cells). Forsuch cells there is never any “rest” and the “resting potential” is a theoretical concept. Other cellswith little in the way of membrane transport functions that change with time have a restingmembrane potential that can be measured by inserting an electrode into the cell. Transmembranepotentials can also be measured optically with dyes that change their optical properties according tothe membrane potential.

Summary of resting potential values in different types of cells

The resting membrane potential in different cell types are approximately:

Skeletal muscle cells: −95 mV Smooth muscle cells: -50mV Astroglia: -80/-90mV Neurons: -70mV



Generator and Graded potentials

Differences in concentration of ions on opposite sides of a cellular membrane produce a voltagedifference called the membrane potential. The largest contributions usually come from sodium(Na+) and chloride (Cl–) ions which have high concentrations in the extracellular region, andpotassium (K+) ions, which along with large protein anions have high concentrations in theintracellular region. Calcium ions, which sometimes play an important role, are not shown.

Membrane potential (or transmembrane potential) is the difference in voltage (or electricalpotential difference) between the interior and exterior of a cell (Vinterior − Vexterior). All animal cellsare surrounded by a plasma membrane composed of a lipid bilayer with many diverse proteinassemblages embedded in it. The fluid on both sides of the membrane contains high concentrationsof mobile ions, of which sodium (Na+), potassium (K+), chloride (Cl–), and calcium (Ca2+) are themost important. The membrane potential arises from the interaction of ion channels and ion pumpsembedded in the membrane, which maintain different ion concentrations on the intracellular andextracellular sides of the membrane.

The membrane potential has two basic functions. First, it allows a cell to function as a battery,providing power to operate a variety of "molecular devices" embedded in the membrane. Second,in electrically excitable cells such as neurons, it is used for transmitting signals between differentparts of a cell. Opening or closing of ion channels at one point in the membrane produces a localchange in the membrane potential, which causes electric current to flow rapidly to other points inthe membrane.

In non-excitable cells, and in excitable cells in their baseline states, the membrane potential is heldat a relatively stable value, called the resting potential. For neurons, typical values of the restingpotential range from -70 to -80 millivolts; that is, the interior of a cell has a negative baselinevoltage of a bit less than one tenth of a volt. Opening and closing of ion channels can induce adeparture from the resting potential, called a depolarization if the interior voltage rises (say from -70 mV to -65 mV), or a hyperpolarization if the interior voltage becomes more negative (changingfrom -70 mV to -80 mV, for example). In excitable cells, a sufficiently large depolarization canevoke a short-lasting all-or-nothing event called an action potential, in which the membranepotential very rapidly undergoes a large change, often briefly reversing its sign. Action potentialsare generated by special types of voltage-dependent ion channels.

In neurons, the factors that influence the membrane potential are diverse. They include numeroustypes of ion channels, some that are chemically gated and some that are voltage-gated. Becausevoltage-dependent ion channels are controlled by the membrane potential, while the membranepotential itself is partly controlled by these same ion channels, feedback loops arise which allow forcomplex temporal dynamics, including oscillations and regenerative events such as actionpotentials.

Physical basis

The membrane potential in a cell derives ultimately from two factors: electrical force and diffusion.Electrical force arises from the mutual attraction between particles with opposite electrical charges(positive and negative) and the mutual repulsion between particles with the same type of charge(both positive or both negative). Diffusion arises from the statistical tendency of particles to



redistribute from regions where they are highly concentrated to regions where the concentration islow.

Voltage

Voltage, which is synonymous with electrical potential, is relatively simple to definemathematically, but not easy to explain concretely in a non-mathematical way. Intuitively, voltageis the ability to drive an electrical current. If a voltage source such as a battery is placed in anelectrical circuit, the higher the voltage of the source, the greater the amount of current that it willdrive. In a functioning circuit, each point can be assigned a voltage level—the voltage differencebetween any two points determines the amount of current that would flow through a wire hookeddirectly from one point to the other. In practical electronics, the voltage difference between twopoints can be measured by connecting them to the two leads of a volt meter (voltmeter).

The functional significance of voltage lies only in voltage differences—the absolute value ofvoltage has no significance. A volt meter can measure the voltage difference between two locationsin a circuit, but there is no instrument that can measure the voltage at a single point: the concept hasno meaning. It is conventional in electronics to assign a voltage of zero to some arbitrarily chosenelement of the circuit, and then assign voltages for other elements on the basis of the measured orcalculated voltage differences, but there is no significance in which element is chosen as the zeropoint—the function of a circuit depends only on the differences, not on voltages per se.

The same principle applies to voltage in cell biology. In electrically active tissue, the voltagedifference between any two points can be measured by inserting an electrode at each point andconnecting both electrodes to the leads of a volt meter. There is no way, however, to measure thevoltage of a single point. Thus, a statement that the voltage difference across the membrane of acell is 60 millivolts can be verified by placing electrodes inside and outside the cell—but whetherthe exterior is assigned a voltage of 60 mV and the interior 0 mV, or the exterior is assigned avoltage of 0 mV and the interior -60 mV, has no significance; only the difference between the twomatters, not the absolute number assigned to either.

In mathematical terms, the definition of voltage begins with the concept of an electric field E, avector field assigning a magnitude and direction to each point in space. In many situations, theelectric field is a conservative field, which means that it can be expressed as the gradient of a scalarfunction V, that is, E = ∇V. This scalar field V is referred to as the voltage distribution. Note that thedefinition allows for an arbitrary constant of integration—this is why absolute values of voltage arenot meaningful. In general electric fields can only be treated as conservative if magnetic fields donot significantly influence them, but this condition usually applies well to biological tissue.

Because the electric field is the gradient of the voltage distribution, rapid changes in voltage withina small region imply a strong electric field; conversely, if the voltage remains approximately thesame over a large region, the electric fields in that region must be weak. A strong electric field,equivalent to a strong voltage gradient, implies that a strong force is exerted on any chargedparticles that lie within the region.



Salts and ions in an aqueous medium

The fluid both inside and outside of animal cells (intracellular and extracellular) contains a highconcentration of dissolved salts. When salts dissolve in water, they break apart into ions—forexample sodium chloride (NaCl) breaks up almost entirely into positively charged sodium ions(Na+) and negatively charged chloride (Cl–) ions. Small ions such as sodium (Na+), potassium (K+),calcium (Ca++), and chloride (Cl–) are present in high concentrations, and are capable of diffusingfreely from place to place, unless some type of barrier impedes them.

Plasma membrane

The cell membrane, also called the plasma membrane or plasmalemma, is a semipermeable lipidbilayer common to all living cells. It contains a variety of biological molecules, primarily proteinsand lipids, which are involved in a vast array of cellular processes.

Every animal cell is enclosed in a plasma membrane, which has the structure of a lipid bilayer withmany types of large molecules embedded in it. Because it is made of lipid molecules, the plasmamembrane intrinsically has a high electrical resistivity, in other words a low intrinsic permeabilityto ions. However, some of the molecules embedded in the membrane are capable either of activelytransporting ions from one side of the membrane to the other, or of providing channels throughwhich they can move.

In electrical terminology, the plasma membrane functions as a combined resistor and capacitor.Resistance arises from the fact that the membrane impedes the movement of charges across it.Capacitance arises from the fact that the lipid bilayer is so thin that an accumulation of chargedparticles on one side gives rise to an electrical force that pulls oppositely-charged particles towardthe other side. The capacitance of the membrane is relatively unaffected by the molecules that areembedded in it, so it has a more or less invariant value estimated at about 2 µF/cm2 (the totalcapacitance of a patch of membrane is proportional to its area). The conductance of a pure lipidbilayer is so low, on the other hand, that in biological situations it is always dominated by theconductance of alternative pathways provided by embedded molecules. Thus the capacitance of themembrane is more or less fixed, but the resistance is highly variable.

The thickness of a plasma membrane is estimated to be about 7-8 nanometers. Because themembrane is so thin, it does not take a very large transmembrane voltage to create a strong electricfield within it. Typical membrane potentials in animal cells are on the order of 100 millivolts (thatis, one tenth of a volt), but calculations show that this generates an electric field close to themaximum that the membrane can sustain—it has been calculated that a voltage difference muchlarger than 200 millivolts could cause dielectric breakdown, that is, arcing across the membrane.

Facilitated diffusion and transport

The resistance of a pure lipid bilayer to the passage of ions across it is very high, but structuresembedded in the membrane can greatly enhance ion movement, either actively or passively, viamechanisms called facilitated transport and facilitated diffusion. The two types of structure thatplay the largest roles are ion channels and ion pumps, both usually formed from assemblages ofprotein molecules. Ion channels provide passageways through which ions can move. In most casesan ion channel is only permeable to specific types of ions (for example sodium and potassium but



not chloride or calcium), and sometimes the permeability varies depending on the direction of ionmovement. Ion pumps, also known as ion transporters or carrier proteins, actively transport specifictypes of ions from one side of the membrane to the other, sometimes using energy derived frommetabolic processes to do so.

Ion pumps

A major contribution to establishing the membrane potential is made by the sodium-potassiumexchange pump. This is a complex of proteins embedded in the membrane that derives energy fromATP in order to transport sodium and potassium ions across the membrane. On each cycle, thepump exchanges three Na+ ions from the intracellular space for two K+ ions from the extracellularspace. If the numbers of each type of ion were equal, the pump would be electrically neutral, butbecause of the three-for-two exchange, it gives a net movement of one positive charge fromintracellular to extracellular for each cycle, thereby contributing to a positive voltage difference.The pump has three effects: (1) it makes the sodium concentration high in the extracellular spaceand low in the intracellular space; (2) it makes the potassium concentration high in the intracellularspace and low in the extracellular space; (3) it gives the extracellular space a positive voltage withrespect to the intracellular space.

The sodium-potassium exchange pump is relatively slow in operation. If a cell were initialized withequal concentrations of sodium and potassium everywhere, it would take hours for the pump toestablish equilibrium. The pump operates constantly, but becomes progressively less efficient as theconcentrations of sodium and potassium available for pumping are reduced.

Another functionally important ion pump is the sodium-calcium exchanger. This pump operates ina conceptually similar way to the sodium-potassium pump, except that in each cycle it exchangesthree Na+ from the extracellular space for one Ca++ from the intracellular space. Because the netflow of charge is inward, this pump runs "downhill", effectively, and therefore does not require anyenergy source except the membrane voltage. Its most important effect is to pump calciumoutward—it also allows an inward flow of sodium, thereby counteracting the sodium-potassiumpump, but because overall sodium and potassium concentrations are much higher than calciumconcentrations, this effect is relatively unimportant. The net result of the sodium-calcium exchangeris that in the resting state, intracellular calcium concentrations become very low.

Ion channels

As explained above, a pure lipid bilayer has a very low permeability to ions of any type. However,animal cell membranes contain a very diverse set of ion channels, which are protein structuresembedded in the membrane that allow passage of specific types of ions under specific conditions.These can be divided into three types: leakage channels, ligand-gated channels, and voltage-dependent channels. This categorization is not exhaustive—it leaves out sensory receptors, many ofwhich depend on ion channels that are activated by physical stimuli such as light, temperature, orstretching.

Leakage channels

Leakage channels are the simplest type, in that their permeability is more or less constant. Thetypes of leakage channels that have the greatest significance in neurons are potassium and chloride



channels. It should be noted that even these are not perfectly constant in their properties: first, mostof them are voltage-dependent in the sense that they conduct better in one direction than the other(in other words, they are rectifiers); second, some of them are capable of being shut off by chemicalligands even though they do not require ligands in order to operate.

Ligand-gated channels

Ligand-gated ion channels are channels whose permeability is greatly increased when some type ofchemical ligand binds to the protein structure. Animal cells contain hundreds, if not thousands, oftypes of these. A large subset function as neurotransmitter receptors—they occur at postsynapticsites, and the chemical ligand that gates them is released by the presynaptic axon terminal. Oneexample of this type is the AMPA receptor, a receptor for the neurotransmitter glutamate that whenactivated allows passage of sodium and potassium ions. Another example is the GABAA receptor, areceptor for the neurotransmitter GABA that when activated allows passage of chloride ions.

Neurotransmitter receptors are activated by ligands that appear in the extracellular area, but thereare other types of ligand-gated channels that are controlled by interactions on the intracellular side.

Voltage-dependent channels

Voltage-gated ion channels, also known as voltage dependent, are channels whose permeability isinfluenced by the membrane potential. They form another very large group, with each memberhaving a particular ion selectivity and a particular voltage dependence. Many are also time-dependent—in other words, they do not respond immediately to a voltage change, but only after adelay.

One of the most important members of this group is a type of voltage-gated sodium channel thatunderlies action potentials—these are sometimes called Hodgkin-Huxley sodium channels becausethey were initially characterized by Alan Lloyd Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the physiology of the action potential. The channel is closed at the restingvoltage level, but opens abruptly when the voltage exceeds a certain threshold, allowing a largeinflux of sodium ions that produces a very rapid change in the membrane potential. Recovery froman action potential is partly dependent on a type of voltage-gated potassium channel which is closedat the resting voltage level but opens as a consequence of the large voltage change produced duringthe action potential.

Some voltage-dependent ion channels are also at the same time ligand-gated. One of the bestknown of these is the NMDA receptor, a type of calcium channel that is gated by theneurotransmitter glutamate but also requires the membrane potential to be elevated substantiallyabove baseline in order to open.

Reversal potential

The reversal potential (or equilibrium potential) of an ion is the value of transmembrane voltage atwhich diffusive and electrical forces counterbalance, so that there is no net ion flow across themembrane. This means that the transmembrane voltage exactly opposes the force of diffusion of theion , such that the net current of the ion across the membrane is zero and unchanging. The reversal



potential is important because it gives the voltage that acts on channels permeable to that ion—inother words, it gives the voltage that the

Equivalent circuit

Electrophysiologists model the effects of ionic concentration differences, ion channels, andmembrane capacitance in terms of an equivalent circuit, which is intended to represent the electricalproperties of a small patch of membrane. The equivalent circuit consists of a capacitor in parallelwith four pathways each consisting of a battery in series with a variable conductance. Thecapacitance is determined by the properties of the lipid bilayer, and is taken to be fixed. Each of thefour parallel pathways comes from one of the principal ions, sodium, potassium, chloride, andcalcium. The voltage of each ionic pathway is determined by the concentrations of the ion on eachside of the membrane; see the Reversal potential section below. The conductance of each ionicpathway at any point in time is determined by the states of all the ion channels that are potentiallypermeable to that ion, including leakage channels, ligand-gated channels, and voltage-dependentchannels.

Reduced circuit obtained by combining the ion-specific pathways using the Goldman equation

For fixed ion concentrations and fixed values of ion channel conductance, the equivalent circuit canbe further reduced, using the Goldman equation as described below, to a circuit containing acapacitance in parallel with a battery and conductance. Electrically this is a type of RC circuit(resistance-capacitance circuit), and its electrical properties are very simple. Starting from anyinitial state, the current flowing across either the conductance or capacitance decays with anexponential time course, with a time constant of τ = RC, where C is the capacitance of themembrane patch, and R = 1/gnet is the net resistance. For realistic situations the time constantusually lies in the 1—100 millisecond range. In most cases changes in the conductance of ionchannels occur on a faster time scale, so an RC circuit is not a good approximation; however thedifferential commonly equation used to model a membrane patch is a modified version of the RCcircuit equation.

Graded potentials

As explained above, the membrane potential at any point in a cell's membrane is determined by theion concentration differences between the intracellular and extracellular areas, and by thepermeability of the membrane to each type of ion. The ion concentrations do not normally changevery quickly (with the exception of calcium, where the baseline intracellular concentration is so lowthat even a small inflow may increase it by orders of magnitude), but the permeabilities can changein a fraction of a millisecond, as a result of activation of ligand-gated or voltage-gated ion channels.The change in membrane potential can be large or small, depending on how many ion channels areactivated and what type they are. Changes of this type are referred to as graded potentials, incontrast to action potentials, which have a fixed amplitude and time course.

As can be derived from the Goldman equation shown above, the effect of increasing thepermeability for a particular type of ion is to shift the membrane potential toward the reversalpotential for that ion. Thus, opening sodium channels pulls the membrane potential toward thesodium reversal potential, usually around +100 mV. Opening potassium channels pulls themembrane potential toward about -90 mV; opening chloride channels pulls it toward about -70 mV.



Because -90 to +100 mV is the full operating range of membrane potential, the effect is that sodiumchannels always pull the membrane potential up, potassium channels pull it down, and chloridechannels pull it toward the resting potential.

Graded membrane potentials are particularly important in neurons, where they are produced bysynapses—a temporary rise or fall in membrane potential produced by activation of a synapse iscalled a postsynaptic potential. Neurotransmitters that act to open sodium channels cause themembrane potential to rise, while neurotransmitters that act on potassium channels cause it to fall.Because the membrane potential in a neuron must rise past the threshold value to produce an actionpotential, a rise in membrane potential is excitatory, while a fall is inhibitory. Thusneurotransmitters that act to open sodium channels produce a so-called excitatory postsynapticpotential, or EPSP, whereas neurotransmitters that act to open potassium channels produce aninhibitory postsynaptic potential, or IPSP. When multiple types of channels are open within thesame time period, their postsynaptic potentials summate.

All other values of membrane potential

From the viewpoint of biophysics, there is nothing particularly special about the resting membranepotential. It is merely the membrane potential that results from the membrane permeabilities thatpredominate when the cell is resting. The above equation of weighted averages always applies, butthe following approach may be easier to visualize. At any given moment, there are two factors foran ion that determine how much influence that ion will have over the membrane potential of a cell.

1. That ion's driving force and,

2. That ion's permeability

Intuitively, this is easy to understand. If the driving force is high, then the ion is being "pushed"across the membrane hard (more correctly stated: it is diffusing in one direction faster than theother). If the permeability is high, it will be easier for the ion to diffuse across the membrane. Butwhat are 'driving force' and 'permeability'?

Driving force: the driving force is the net electrical force available to move that ion acrossthe membrane. It is calculated as the difference between the voltage that the ion "wants" tobe at (its equilibrium potential) and the actual membrane potential (Em). So formally, thedriving force for an ion = Em - Eion

For example, at our earlier calculated resting potential of −73 mV, the driving force onpotassium is 7 mV (−73 mV) − (−80 mV) = 7 mV. The driving force on sodium would be(−73 mV) − (60 mV) = −133 mV.

Permeability: is simply a measure of how easily an ion can cross the membrane. It isnormally measured as the (electrical) conductance and the unit, siemens, corresponds to 1C·s−1·V−1, that is one charge per second per volt of potential.



So in a resting membrane, while the driving force for potassium is low, its permeability is veryhigh. Sodium has a huge driving force, but almost no resting permeability. In this case, the mathtells us that potassium carries about 20 times more current than sodium, and thus has 20 times moreinfluence over Em than does sodium.

However, consider another case—the peak of the action potential. Here permeability to Na is highand K permeability is relatively low. Thus the membrane moves to near ENa and far from EK.

The more ions are permeant, the more complicated it becomes to predict the membrane potential.However, this can be done using the Goldman-Hodgkin-Katz equation or the weighted meansequation. By simply plugging in the concentration gradients and the permeabilities of the ions atany instant in time, one can determine the membrane potential at that moment. What the GHKequations says, basically, is that at any time, the value of the membrane potential will be a weightedaverage of the equilibrium potentials of all permeant ions. The "weighting" is the ions relativepermeability across the membrane.

Effects and implications

While cells expend energy to transport ions and establish a transmembrane potential, they use thispotential in turn to transport other ions and metabolites such as sugar. The transmembrane potentialof the mitochondria drives the production of ATP, which is the common currency of biologicalenergy.

Cells may draw on the energy they store in the resting potential to drive action potentials or otherforms of excitation. These changes in the membrane potential enable communication with othercells (as with action potentials) or initiate changes inside the cell, which happens in an egg when itis fertilized by a sperm.

In neuronal cells, an action potential begins with a rush of sodium ions into the cell through sodiumchannels, resulting in depolarization, while recovery involves an outward rush of potassiumthrough potassium channels. Both these fluxes occur by passive diffusion.

Synapse

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical orchemical signal to another cell. The word "synapse" comes from "synaptein", which Sir CharlesScott Sherrington and colleagues coined from the Greek "syn-" ("together") and "haptein" ("toclasp").

Synapses are essential to neuronal function: neurons are cells that are specialized to pass signals toindividual target cells, and synapses are the means by which they do so. At a synapse, the plasmamembrane of the signal-passing neuron (the presynaptic neuron) comes into close apposition withthe membrane of the target (postsynaptic) cell. Both the presynaptic and postsynaptic sites containextensive arrays of molecular machinery that link the two membranes together and carry out thesignaling process. In many synapses, the presynaptic part is located on an axon, but somepresynaptic sites are located on a dendrite or soma.



There are two fundamentally different types of synapse:

In a chemical synapse, the presynaptic neuron releases a chemical called a neurotransmitterthat binds to receptors located in the postsynaptic cell, usually embedded in the plasmamembrane. Binding of the neurotransmitter to a receptor can affect the postsynaptic cell in awide variety of ways.

In an electrical synapse, the presynaptic and postsynaptic cell membranes are connected bychannels that are capable of passing electrical current, causing voltage changes in thepresynaptic cell to induce voltage changes in the postsynaptic cell.

Neurotransmitter

Neurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cellacross the synapse. Neurotransmitters are packaged into synaptic vesicles that cluster beneath themembrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where theybind to receptors in the membrane on the postsynaptic side of the synapse. Release ofneurotransmitters usually follows arrival of an action potential at the synapse, but may followgraded electrical potentials. Low level "baseline" release also occurs without electrical stimulation.

Discovery

In the early 20th century, scientists assumed that synaptic communication was electrical. However,through the careful histological examinations of Ramón y Cajal (1852–1934), a 20 to 40 nm gapbetween neurons, known today as the synaptic cleft, was discovered and cast doubt on thepossibility of electrical transmission. In 1921, German pharmacologist Otto Loewi (1873–1961)confirmed the notion that neurons communicate by releasing chemicals. Through a series ofexperiments involving the vagus nerves of frogs, Loewi was able to manually control the heart rateof frogs by controlling the amount of saline solution present around the vagus nerve. Uponcompletion of this experiment, Loewi asserted that neurons do not communicate with electricsignals but rather through the change in chemical concentrations. Furthermore, Otto Loewi isaccredited with discovering acetylcholine—the first known neurotransmitter.

Identifying neurotransmitters

Some of the properties that define a chemical as a neurotransmitter are difficult to testexperimentally. For example, it is easy using an electron microscope to recognize vesicles on thepresynaptic side of a synapse, but it may not be easy to determine directly what chemical is packedinto them. The difficulties led to many historical controversies over whether a given chemical wasor was not clearly established as a transmitter. In an effort to give some structure to the arguments,neurochemists worked out a set of experimentally tractable rules. According to the prevailingbeliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the followingconditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of thesynapse.

The chemical is present in the presynaptic element.



It is available in sufficient quantity in the presynaptic neuron to affect the postsynapticneuron;

There are postsynaptic receptors and the chemical is able to bind to them.

A biochemical mechanism for inactivation is present.

Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced theimportance of these rules. A series of experiments that may have taken several years in the 1960scan now be done, with much better precision, in a few months. Thus, it is unusual nowadays for theidentification of a chemical as a neurotransmitter to remain controversial for very long.

Types of neurotransmitters

There are many different ways to classify neurotransmitters. Dividing them into amino acids,peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine

Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine(adrenaline), histamine, serotonin (SE, 5-HT), melatonin

Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly.Many of these are "co-released" along with a small-molecule transmitter, but in some cases apeptide is the primary transmitter at a synapse.

Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, asare some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). These are notclassical neurotransmitters by the strictest definition, however, because although they have all beenshown experimentally to be released by presynaptic terminals in an activity-dependent way, theyare not packaged into vesicles.

By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of thesynapses in the human brain. The next most prevalent is GABA, which is inhibitory at more than90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewersynapses, they may be very important functionally—the great majority of psychoactive drugs exerttheir effects by altering the actions of some neurotransmitter systems, often acting throughtransmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamineexert their effects primarily on the dopamine system. The addictive opiate drugs exert their effectsprimarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only directeffect of a neurotransmitter is to activate one or more types of receptors. The effect on thepostsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for



some neurotransmitters (for example, glutamate), the most important receptors all have excitatoryeffects: that is, they increase the probability that the target cell will fire an action potential. Forother neurotransmitters (such as GABA), the most important receptors all have inhibitory effects.There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory andinhibitory receptors exist; and there are some types of receptors that activate complex metabolicpathways in the postsynaptic cell to produce effects that cannot appropriately be called eitherexcitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory orinhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory thatthis usage is seen very frequently.

Actions

As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore,the effects of a neurotransmitter system depend on the connections of the neurons that use thetransmitter, and the chemical properties of the receptors that the transmitter binds to.

Here are a few examples of important neurotransmitter actions:

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinalcord. It is also used at most synapses that are "modifiable", i.e. capable of increasing ordecreasing in strength. Modifiable synapses are thought to be the main memory-storageelements in the brain.

GABA is used at the great majority of fast inhibitory synapses in virtually every part of thebrain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.Correspondingly glycine is the inhibitory transmitter in the spinal cord.

Acetylcholine is distinguished as the transmitter at the neuromuscular junction connectingmotor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission atthese synapses. Acetylcholine also operates in many regions of the brain, but using differenttypes of receptors.

Dopamine has a number of important functions in the brain. It plays a critical role in thereward system, but dysfunction of the dopamine system is also implicated in Parkinson'sdisease and schizophrenia.

Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine(approximately 90%), and the remainder in central nervous system neurons. It functions toregulate appetite, sleep, memory and learning, temperature, mood, behaviour, musclecontraction, and function of the cardiovascular system and endocrine system. It isspeculated to have a role in depression, as some depressed patients are seen to have lowerconcentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.

Substance P undecapeptide responsible for transmission of pain from certain sensoryneurons to the central nervous system.

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, whereactivation of the system affects large volumes of the brain, called volume transmission. Majorneurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system,the serotonin system and the cholinergic system.



Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains thecomplexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine backinto the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap longer.Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to thereceptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addictionto cocaine may result from prolonged exposure to excess dopamine in the synapses, causing thebody to down-regulate some postsynaptic receptors. After the effects of the drug wear off, onemight feel depressed because of the decreased probability of the neurotransmitter binding to areceptor. Prozac is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake ofserotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse andallows it to remain there longer, hence potentiating the effect of naturally released serotonin.AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpineprevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-Band thus increases dopamine levels.

Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at leastin part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantianigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected,with moderate success.

A brief comparison of the major neurotransmitter systems follows:

Neurotransmitter systems

System Origin Effects

Noradrenalinesystem

locus coeruleus arousal

rewardLateral tegmental field

Dopamine system

dopamine pathways:

mesocortical pathway

mesolimbic pathway

nigrostriatal pathway

tuberoinfundibularpathway

motor system, reward, cognition,endocrine, nausea

Serotonin systemcaudal dorsal raphe nucleus Increase (introversion), mood, satiety,

body temperature and sleep, whiledecreasing nociception.rostral dorsal raphe nucleus

Cholinergic system

pontomesencephalotegmentalcomplex learning

short-term memory

arousal

reward

basal optic nucleus of Meynert

medial septal nucleus



Common neurotransmitters

Category Name

Abbreviation

Metabotropic

Ionotropic

Small: Amino acids Aspartate - -

NeuropeptidesN-Acetylaspartylglutamate

NAAG

Metabotropicglutamatereceptors; selectiveagonist of mGluR3

-

Small: Amino acidsGlutamate (glutamicacid)

GluMetabotropicglutamate receptor

NMDAreceptor,Kainatereceptor,AMPA receptor

Small: Amino acidsGamma-aminobutyricacid

GABA GABAB receptorGABAA,GABAA-ρreceptor

Small: Amino acids Glycine Gly -Glycinereceptor

Small:Acetylcholine

Acetylcholine AchMuscarinicacetylcholinereceptor

Nicotinicacetylcholinereceptor

Small: Monoamine(Phe/Tyr)

Dopamine DA Dopamine receptor -


Norepinephrine(noradrenaline)

NEAdrenergicreceptor

-


Epinephrine (adrenaline) EpiAdrenergicreceptor

-


Octopamine - -


Tyramine -



Small: Monoamine(Trp)

Serotonin (5-hydroxytryptamine)

5-HTSerotonin receptor,all but 5-HT3

5-HT3

Small: Monoamine(Trp)

Melatonin Mel Melatonin receptor -

Small: Monoamine(His)

Histamine H Histamine receptor -

PP: Gastrins Gastrin - -

PP: Gastrins Cholecystokinin CCKCholecystokininreceptor

-

PP:Neurohypophyseals

Vasopressin AVPVasopressinreceptor

-


Oxytocin OT Oxytocin receptor -


Neurophysin I - -


Neurophysin II - -

PP: Neuropeptide Y Neuropeptide Y NYNeuropeptide Yreceptor

-

PP: Neuropeptide Y Pancreatic polypeptide PP - -

PP: Neuropeptide Y Peptide YY PYY - -

PP: OpioidsCorticotropin(adrenocorticotropichormone)

ACTHCorticotropinreceptor

-

PP: Opioids Dynorphin - -

PP: Opioids Endorphin - -

PP: Opioids Enkephaline - -

PP: Secretins Secretin Secretin receptor -



PP: Secretins Motilin Motilin receptor -

PP: Secretins Glucagon Glucagon receptor -

PP: SecretinsVasoactive intestinalpeptide

VIPVasoactiveintestinal peptidereceptor

-

PP: SecretinsGrowth hormone-releasing factor

GRF - -

PP: Somtostatins SomatostatinSomatostatinreceptor

-

SS: Tachykinins Neurokinin A - -

SS: Tachykinins Neurokinin B - -

SS: Tachykinins Substance P - -

PP: Other Bombesin - -

PP: Other Gastrin releasing peptide GRP - -

Gas Nitric oxide NOSoluble guanylylcyclase

-

Gas Carbon monoxide CO -Heme bound topotassiumchannels

Other Anandamide AEACannabinoidreceptor

-

Other Adenosine triphosphate ATP P2Y12 P2X receptor

Precursors of neurotransmitters

While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence ismixed as to whether neurotransmitter release (firing) is increased. Even with increasedneurotransmitter release, it is unclear whether this will result in a long-term increase inneurotransmitter signal strength, since the nervous system can adapt to changes such as increasedneurotransmitter synthesis and may therefore maintain constant firing. Some neurotransmitters mayhave a role in depression, and there is some evidence to suggest that intake of precursors of theseneurotransmitters may be useful in the treatment of mild and moderate depression.



Norepinephrine precursors

For depressed patients where low activity of the neurotransmitter norepinephrine is implicated,there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine.These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studiessuggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much roomfor further research in this area.

Serotonin precursors

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production ofserotonin in the brain. It is significantly more effective than a placebo in the treatment of mild andmoderate depression. This conversion requires vitamin C.

5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placeboand nearly as effective or of equal effectiveness to some antidepressants. Interestingly, it takes lessthan 2 weeks for an antidepressant response to occur, while antidepressant drugs generally take 2–4weeks. 5-HTP also has no significant side effects.

Administration of 5-HTP bypasses the rate-limiting step in the synthesis of serotonin fromtryptophan. Also, 5-HTP readily passes through the blood-brain barrier, and enters the centralnervous system without need of a transport molecule. Note, however, that there is some evidence tosuggest that a postsynaptic defect in serotonin utilization may be an important factor in depression,not only insufficient serotonin.

It is important to note that not all cases of depression are caused by low levels of serotonin.However, in the subgroup of depressed patients that are serotonin-deficient, there is strong evidenceto suggest that 5-HTP is therapeutically useful in treating depression, and more useful than L-tryptophan.

Depression does not have one cause; not all cases of depression are due to low levels of serotoninor norepinephrine. Blood tests for the ratio of tryptophan to other amino acids, as well as red bloodcell membrane transport of these amino acids, can be predictive of whether serotonin ornorepinephrine would be of therapeutic benefit. Overall, there is evidence to suggest thatneurotransmitter precursors may be useful in the treatment of mild and moderate depression.

Degradation and elimination

Neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent furtherexcitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatoryneurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and recycledby the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine areable to diffuse away from their targeted synaptic junctions and are eliminated from the body via thekidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways atregulatory points, which may be the target of the body's own regulatory system or recreationaldrugs.



Polysynaptic Reflex

A reflex action that involves an electrical impulse being transferred from a sensory neuron to amotor neuron via at least one connecting neuron (interneuron) in the spinal cord. For example,stimulation of pain receptors in the skin initiates a withdrawal reflex, which involves severalsynapses with several motor neurons and results in the removal of the organism or part from thestimulus.

Effects of drug on Behaviour

The human brain is the most complex organ in the body. This three-pound mass of gray and whitematter sits at the center of all human activity - you need it to drive a car, to enjoy a meal, to breathe,to create an artistic masterpiece, and to enjoy everyday activities. In brief, the brain regulates yourbasic body functions; enables you to interpret and respond to everything you experience; andshapes your thoughts, emotions, and behavior.

The brain is made up of many parts that all work together as a team. Different parts of the brain areresponsible for coordinating and performing specific functions. Drugs can alter important brainareas that are necessary for life-sustaining functions and can drive the compulsive drug abuse thatmarks addiction. Brain areas affected by drug abuse -

The brain stem controls basic functions critical to life, such as heart rate, breathing, andsleeping.

The limbic system contains the brain's reward circuit - it links together a number of brainstructures that control and regulate our ability to feel pleasure. Feeling pleasure motivates usto repeat behaviors such as eating - actions that are critical to our existence. The limbicsystem is activated when we perform these activities - and also by drugs of abuse. Inaddition, the limbic system is responsible for our perception of other emotions, bothpositive and negative, which explains the mood-altering properties of many drugs.

The cerebral cortex is divided into areas that control specific functions. Different areas processinformation from our senses, enabling us to see, feel, hear, and taste. The front part of the cortex,the frontal cortex or forebrain, is the thinking center of the brain; it powers our ability to think,plan, solve problems, and make decisions.

Here are summaries of the effect of selected drugs on the behaviour

Heroin

Heroin is a highly addictive opiate (like morphine). Brain cells can become dependent (highlyaddictive) on this drug to the extent that users need it in order to function in their daily routine.While heroin use starts out with a rush of pleasure, it leaves the use in a fog for many hoursafterwards. Users soon find that their sole purpose in life is to have more of the drug that their bodyhas become dependant on.



Marijuana

The parts of the brain that control emotions, memory, and judgment are affected bymarijuana. Smoking it can not only weaken short-term memory, but can block information frommaking it into long term memory. It has also been shown to weaken problem solving ability.

Alcohol

Alcohol is no safer than drugs. Alcohol impairs judgment and leads to memory lapses. It can lead toblackouts. It distorts vision, shortens coordination, and in addition to the brain can damage everyother organ in the body.

Cocaine

Cocaine, both in powder form and as crack, is an extremely addictive stimulant. An addict usuallyloses interest in many areas of life, including school, sports, family, and friends. Use of cocaine canlead to feelings of paranoia and anxiety. Although often used to enhance sex drive, physical effectof cocaine on the receptors in the brain reduce the ability to feel pleasure (which in turn causes thedependency on the drug).

Inhalants

Inhalants, such as glue, gasoline, hair spray, and paint thinner, are sniffed. The effect on the brain isalmost immediate. And while some vapors leave the body quickly, others will remain for a longtime. The fatty tissues protecting the nerve cells in the brain are destroyed by inhalant vapors. Thisslows down or even stops neural transmissions. Effects of inhalants include diminished ability tolearn, remember, and solve problems.

LSD

While some people use LSD for the sense of enhanced and vivid sensory experience, it can causeparanoia, confusion, anxiety, and panic attacks. Like Ecstasy, the user often blurs reality andfantasy, and has a distorted view of time and distance.

Steroids

Anabolic steroids are used to improve athletic performance and gain muscle bulk. Unfortunately,steroids cause moodiness and can permanently impair learning and memory abilities.

Tobacco

Tobacco is a dangerous drug, putting nicotine into your body. Nicotine affects the brain quickly,like other inhalants, producing feelings of pleasure, like cocaine, and is highly addictive, likeheroin.



Methamphetamine

Known on the street as meth, speed, chalk, ice, crystal, and glass, methamphetamine is an addictivestimulant that strongly activates certain systems in the brain.

Ritalin

This drug is often prescribed to treat attention deficit disorder. It is becoming an illicit street drug aswell. Drug users looking for a high will crush Ritalin into a powder and snort it like cocaine, orinject it like heroin. It then has a much more powerful effect on the body. It causes severeheadaches, anxiety, paranoia, and delusions.

References:

1. Scheider, A.M. & Tatshis, B.(1998), Physiological Psychology(3rd ed), RandomHouse, N.Y.

2. Leukal ,F.(2000), Introduction of Physiological Psychology(3rd ed), CBS Publishers,New Delhi.

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