NEUROCHEMISTRY

DEFINTION

Neurochemistry includes the study of neurochemicals influencing the function of neurons and forming the network of neural

operation

HISTORY

• PREVIOUS CONCEPT:

Messages are sent electrically through neurons

• NEW CONCEPT:

B. Otto Lowei and Henry Dale proved messages were sent chemically

Won the Nobel Prize in 1936 for their dicovery

MOLECULAR NEUROSCIENCE

• Molecular neuroscience observes concepts in molecular biology applied to the nervous systems of animals. • Molecular neuroanatomy

• Mechanisms of molecular neurosignaling

• Effects of genetics on neuronal development

• Molecular basis for neuroplasticity and neurodegenerative diseases

NEUROANATOMY

• Main components include:• Brain

• Neurons

• Synapse

• Neuroglia

NEURONS

• Cell body – metabolism, protein synthesis

• Dendrites (input structure)

receive inputs from other neurons

perform spatio-temporal integration of inputs

relay information to the cell body

• Axon (output structure)

a branching fiber that carries the message (spikes) from the cell to other neurons

SYNAPSES

• Site of communication between two neurons formed when an axon of a presynaptic cell connects with the dendrites of a postsynaptic cell

• A synapse can be excitatory or inhibitory:

• Excitatory:

activity at an excitatory synapse depolarizes the local membrane potential of the postsynaptic cell and makes the cell more prone to firing; usually connects on dendrite

• Inhibitory

activity at an inhibitory synapse hyperpolarizes the local membrane potential of the postsynaptic cell and makes it less prone to firing: usually connects on cell body

• The greater the synaptic strength, the greater the depolarization or hyperpolarization

CHEMICAL IMPULSE

• The messengers are neurotransmitters

• Unidirectional, Relatively slow

• Can respond to multiple messengers

• One neuron can react to multiple others via chemical impulse simultaneously

• Is usually found to occur in variety of signals

• Chemical messenger is secreted from cytoplasm to reach to the next

• Synaptic gap junction is much larger in this case

ELECTRICAL IMPULSE

• Messengers are ionic particles

• Bidirectional, Relatively fast, More specific

• Usually one neuron can communicate with only one successive neuron

• Occurs in reflex actions, for precision and accuracy

• The pore of gap junction channel is wide enough to allow ions and even signaling molecules to flow from one cell to the next.

• Thus when voltage of one cell changes, ions may move through from one cell to the next, carrying positive charge with them and depolarizing the postsynaptic cell.  

NEUROTRANSMITTER LOCATING

• Neurons communicate by chemical transmission across synapses, chemical compounds being neurotransmitters regulate certain vital body functions.

• Neurotransmitters are located by labeling techniques.

• Neural tissue sections are fixed with formaldehyde for detecting Catecholamines (e.g., dopamine), which results in formaldehyde-induced fluorescence after exposing to ultraviolet light

• A targeted neurotransmitter could also be specifically tagged by primary and secondary antibodies with radioactive labeling to identify the neurotransmitter by autoradiography. The presence of neurotransmitters can be observed in ELISA 

NEUROPLASTICITY

“It refers to changes in neural pathways and synapses due to changes in behavior, environment and neural processes, as well as changes resulting from

bodily injury”

• It describes how experiences reorganize neural pathways in the brain.

• Long lasting functional changes in the brain occur when we learn new things or memorize new information.

• These changes in neural connections are called neuroplasticity.

• Falsifies the old concept that the brain is a physiologically static organ

DEVELOPMENTAL PLASTICITY

• After birth, the information in brain from sensory organs of a newborn must be stored in brain processed.

• Nerve cells must make connections with one another, transmitting the impulses to the brain.

• Over the first few years of life, the brain grows rapidly. As each neuron matures, it sends out multiple branches increasing the number of synaptic contacts from neuron to neuron.

• At birth, each neuron in the cerebral cortex has approximately 2,500 synapses. By the time an infant is two or three years old, the number of synapses is approximately 15,000 synapses per neuron (Gopnick, et al., 1999).

• As we age, old connections are deleted through a process called synaptic pruning which eliminates weaker synaptic contacts while stronger connections are kept and strengthened.

• Without a purpose, neurons die through apoptosis

PLASTICITY OF LEARNING AND MEMORY

• Recently, it has been revealed that brain never stops changing and adjusting. 

• Learning, the ability to acquire new knowledge or skills through instruction or experience, causes the brain to change its shape.

• Two types of modifications occur in the brain with learning:1.A change in the internal structure of the neurons, specially in the area of

synapses.2.An increase in the number of synapses between neurons.

• Initially, newly learned data is stored in short-term memory, a series of electrical and chemical events in the brain.

• After a while, information is moved to long-term memory, the result of anatomical or biochemical changes that occur in the brain (Tortora and Grabowski, 1996).

VOLTAGE GATED ION CHANNEL

• Excitable cells have voltage-gated ion channels, present throughout the nervous system in neurons.

• The first ion channels to be characterized were the sodium and potassium ion channels by A.L. Hodgkin and A.F. Huxley in the 1950s upon studying the giant axon of the Loligo genus of squid.

• The three main channels include:

• Sodium ion channel

• Potassium ion channel

• Calcium ion channel

SODIUM ION CHANNEL

• The first voltage-gated ion channels to be isolated in 1984.

• Sodium channels allow an influx of Na+ ions into a neuron, resulting in a depolarization from the resting membrane potential of a neuron to a graded or action potential, depending on the degree of depolarization.

• Sodium channels are known for working in concert with potassium channels during the development of graded potentials and action potentials.

POTASSIUM ION CHANNEL

• Potassium channels occur in many forms in most eukaryotic cells. They tend to stabilize the cell membrane at the potassium equilibrium potential.

• While influx of Na+ ions into a neuron induce cellular depolarization, efflux of K+ ions out of a neuron causes a cell to repolarize to resting membrane potential.

• The activation of potassium ion channels themselves are dependent on the depolarization resulting from Na+ influx during an action potential. Potassium channels were first identified by manipulating molecular genetics (of the flies)

• The presence of potassium channels was first identified in Drosophila melanogaster mutant flies that shook uncontrollably upon anesthesia due to problems in cellular repolarization that led to abnormal neuron.

CALCIUM ION CHANNEL

• Calcium channels play role in cell-signaling cascades as well as neurotransmitter release at axon terminals.

• A variety of different types of calcium ion channels are found in excitable cells.

• Calcium ion channels have been isolated and cloned by chromatographic purification techniques.

• It is notable, as with the case of neurotransmitter release, that calcium channels can interact with intracelluar proteins and plays a strong role in signaling, especially in locations such as the sarcoplasmic reticulum of muscle cells.

NEUROTRANSMITTERS

20

DEFINITION

A chemical released by one neuron that affects another

neuron or an effector organ

(e.g., muscle, gland, blood vessel)

PROPERTIES OF NEUROTRANSMITTERS:

1) Synthesized in the presynaptic neuron

2) Localized to vesicles in the presynaptic neuron

3) Released from the presynaptic neuron under physiological conditions

4) Rabidly removed from the synaptic cleft by uptake or degradation

5) Presence of receptor on the post-synaptic neuron

6) Binding to the receptor elicits a biological response23

25

Neurotransmitters found in the nervous system

EXCITATORY INHIBITORY

Acetylcholine

Aspartate

Dopamine

Histamine

Norepinephrine

Epinephrine

Glutamate

Serotonin

GABA

Glycine

26

Other Neurotransmitters:

Neurotransmitter Derived from Enzyme

Histamine Histidine Histidine decarboxylase

GABA(γ-Amino butyrate)

Glutamate Glutamate decarboxylase

Nitric Oxide Arginine Nitric Oxide Synthase

SIGNAL TRANSDUCTION

DEFINITION

Cells can communicate with each other through a process known as signal transduction.

This involves long strings of chemical messages, often known as signal transduction cascades.

RECEPTORS:

• G protein coupled receptors

• Tyrosine and histidine kinase

• Integrin

G PROTEIN COUPLED RECEPTORS:

• Activates a chain of events

Components:

• Transducer( g-protein)

• Effector(membrane bound enzyme)

• Secondary messenger (c-AMP)

TYPES:

Two major types of G proteins:

• Large heterotrimeric G proteins mediate signal transductions

• Small monomeric G proteins help regulate the cytoskeleton

PATHWAY:

• Ligand binds to the GPCR to cause a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF).

• The GPCR then activates an associated G-protein by exchanging its bound GDP for a GTP.

• The G-protein's α subunit, together with the bound GTP, dissociates from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type.

TYROSINE KINASE:

• Receptor tyrosine kinase are transmembrane proteins with an intercellular kinase domain and extracellular domain that binds ligand.

• Process of dimerization

• The process of dimerization activates the tyrosine kinase region of each individual monomer. Both of these tyrosine kinases adds a phosphate from an ATP molecule to a tyrosine on the tail of the other monomer.

• After this process, the receptor is completely activated and it is then recognized by specific relay proteins located within the cell.

• Each protein binds to a specific phosphorylated tyrosine, leading to a structural alteration which activates the bound protein.

• Each of these activated proteins trigger a transduction pathway, causing the desired cellular response

HISTIDINE KINASE:

• It catalyzes following reaction:

ATP + protein L-histidine -------- ADP + protein N-phospho-L-histidine.

PATHWAY

• The mechanism for the reactions catalyzed by histidine kinase have not been completely elucidated, but current evidence suggests that the catalytic domain of one dimeric unit may rotate in such a way that the ATP binding pocket of that unit can come into contact with a particular histidine residue on the opposite unit and a nucleophilic addition results in a phosphorylated histidine

INTEGRIN

• Integrin family of protein consists of:

• Alpha subtypes

• Beta subtypes

• They function mechanically, by attaching the cell cytoskeleton to the extracellular matrix (ECM), and biochemically, by sensing whether adhesion has occurred.

Integrins function as adhesion receptors for extracellular ligands and transduce biochemical signals into the cell, through downstream effector proteins.

Remarkably, they function bidirectionally, meaning they can transmit information both outside-in and inside-out

49

NEUROENDOCRINE SYSTEM

NEUROENDOCRINOLOGY

DEFINITION:

Neuroendocrinology is the study of the interaction between the nervous system and the endocrine system.

• These systems works together to perform the physiological processes of the human body

MECHANISM

It works when brain specially hypothalamus secrete pituitary gland (master gland). It maintains

Homeostasis

Regulating reproduction

Metabolism

Eating and drinking behaviour

Energy utilization

Blood pressure

INTEGRATION OF NERVOUS AND ENDOCRINE SYSTEM

• Neuroendocrine cells release hormones in the form of neurotransmitters, into the bloodstream in response to transmit signals or impulses from one nerve cell to another nerve cell through nervous system.

• Neuroendocrine system is made up of neuroendocrine cells which are mini factories for producing secretary products; their nerve terminals are large and organized in coherent terminal fields; their output can often be measured easily in the blood

EXAMPLES

Endocrine cells in

• Digestive system regulate intestinal movements and release of digestive enzyme

• Respiratory cells play role in developmental stages of respiratory organs

• Pituitary, pineal and parathyroid glands are neuroendocrine gland

• Adrenal glands are non neuroendocrine glands

AIM AND SCOPE OF NEUROENDOCRINOLOGY

Neuroendocrinology including:

Psychoneuroimmunology

Neuropsychopharmacology 

Reproductive Medicine

Chronobiology

Human Ethology

TECHNIQUES:

There are different techniques used to study neuroendocrinology as:

High-performance liquid chromatography (HPLC) 

Micellar electrokinetic capillary chromatography (MEKC)

Electrical stimulation

Lesioning

Fibre tract cutting

DISORDERS OF NEUROENDOCRINOLOGY

• Every Hormone have specific site for secretion called glands. So it cause disorders at their specific sites. There are various glands working in body which have direct contact with bloodstream. These include:

• Pituitary gland (Master gland)

• pineal gland

• parathyroid glands

DISORDERS OF NEUROENDOCRINOLOGY

Pancreatic neuroendocrine tumors:

• Carcinoid Heart Disease

• Cushing’s Syndrome

• Insulinoma Syndrome 

• Glucagonoma Syndrome

Pituitary Tumor Symptoms:

• Prolactinoma

• Acromegaly 

NEURODEGENERATIVE DISEASES

NEURODEGENERATION

Progressive loss of structure or function of neurons.

Sometimes include death of neurons.

Parkinson’s disease and Alzheimer’s disease occur as a result of neurodegenerative process.

ALZHEIMER’S DISEASE

• It was first described by German psychiatrist and neuropathology’s Alois Alzheimer in 1906 and was named after him.

• It is the common form of dementia.

• Incurable, degenerative and terminal disease.

• It begins with a “pure” impairment of cognitive function.

STAGES OF AD

• Pre-dementia : The most noticeable deficit is memory loss and inability to acquire new information.

• Early: Difficulties with language, executive functions, perception, or execution of movements.

• Moderate: Memory problems increase, the person sometimes can’t recognize close relatives. Long-term memory, which was previously becomes impaired.

• Advanced :The person is completely dependent upon caregivers. Muscle  and mobility deteriorate until they are bedridden, and lose the ability to feed themselves

TREATMENT

• Alzheimer's has no current cure, but treatments for symptoms can temporarily slow the worsening of dementia symptoms and improve quality of life for those with Alzheimer's and the people who take care of them.

MULTIPLE SCLEROSIS

A chronic, progressive neurologic disease characterized by:

“scattered demyelination of nerve fibers in the brain and spinal cord”

MULTIPLE SCLEROSIS INCIDENCE

• Peak onset 20-40 years of age

• 70% between ages 21-40

• Rarely prior to age 10 or after age 60

• F > M (approx. 2:1)

• White > non-white (2:1)

CEREBELLAR SIGNS

• Incoordination

• Slowing of rapid repeating movements

• Scanning speech

• Loss of balance

PARKINSON’S DISEASE

• Researchers don´t know when Parkinson´s disease started but medical scientists have been treating Parkinson´s disease for thousands of years.

• It was known before as the «shaking palsy»

• The first medical text appeared about 2,500 years ago in China.

SYMPTOMS

• Tremors

• Rigidity

• Bradykinesia (slowness in voluntary movement)

• Postural instability

• Anxiety

• Depression

CAUSES

• The lack of dopamine causes the motor symptoms of Parkinson's disease.

• Genetic and pathological studies reveal that inflammation, and stress can contribute to cell damage.

• Scientists suspect that the loss of dopamine is due genetic and environmental factors.

TREATMENT

• Scientists and researchers haven´t found the cure of Parkinson´s Disease.

• People with PD still attend to therapies so that their dopamine levels can increase!

• The most effective therapy is levodopa (Sinemet), because its directly converted into dopamine in the brain.