Overview of Lecture: Nervous systems.see the schedule for reading and watching assignments

Bullet Points: • nervous systems: similar parts, different interactions• organization in vertebrates• developing connections• info processing - reflexes • neurons - resting potentials• integration of information• “decisions” – action potentials• synapses & mechanisms• neurotransmitters• addiction• depression• impulsivity• learning GxE

Learning Goals:

1. Be able to describe the patellar reflex and explain how it creates a negative feedback system that can maintain a postural position without ongoing conscious control.

2. Be able to describe and explain how neurons integrate spatial and/or temporal graded potentials in the dendrites and “make a decision” at the axon hillock.

3. Be able to describe the nature of the action potential that travels down the axon and how it encodes information transmitted to the pre-synaptic terminal.

4. Be able to use an example to describe and explain the roles of neurotransmitters, postsynaptic receptors and presynaptic reuptake pumps in normal synaptic signal transmission. How can a SSRI increase the effective level of serotonin in a synapse. How can prolonged manipulation of a transmitter or transmitter-mimicking drug lead to addiction and withdrawal symptoms when the transmitter/drug is reduced?

5. Be able to describe and explain (briefly and at a very general level) the role of dopamine synaptic signaling in mood (pleasure), addiction, impulsivity (including gambling and not eating marshmallows) and receptivity to positive feedback in education.

Science 26 October 2012:Vol. 338 no. 6106 pp. 475-476 PERSPECTIVE Scott W. EmmonsThe Mood of a Worm

Nervous system function may be understood as the emergent collective property of a networkrather than as the sum of individual circuits. + interactions

This requires identifying all the interactions between the elements. …The human nervous system is a vastly complex network of functionally

interconnected cells whose detailed structure is at present beyond reach. All our actions, calculations, feelings, memories, dreams—consciousness itself—

emerge from its workings. To understand this colossal, enigmatic structure, experimentally amenable model animals with tractable nervous systems many orders of magnitude smaller are studied.

A popular choice has been the worm Caenorhabditis elegans, a nematode 1 mm long with a nervous system containing fewer than 400 neurons. …

Although it is a mistake to consider small invertebrates as primitive, their systems may be closer to the ancestral condition than those of their larger cousins.

Insights into that ancestral condition can help us understand function today.Garrison et al. (1) and Beets et al. (2), add to a growing body of evidence that

even at the highest levels of coordinating fundamental and complex behaviors, the same neural mechanisms are at work in worms and humans.

http://www.sfu.ca/biology/faculty/hutter/hutterlab/research/Ce_nervous_system.html

Animal nervous systems are remarkably similar at the cellular level - how neurons work –

but differ at higher levels of organization,

ex: the structure and function of their brains.

[recall: Sponge Bob has no neurons or brain]

Nervous Systems: (from molecules to mind)

http://faculty.pasadena.edu/dkwon/chap%208_files/textmostly/slide3.html

12 3 4

4

1

Typically, neurons:

1. Gather information

from sensors or other neurons

at the dendritic tree.

2. Integrate information from various

sources as small postsynaptic voltage

changes at the axon hillock

and “decide” whether to send it along

3. Transmit the information

along the axon as voltage action

potentials of varying frequency

4. Neurotransmitters communicate the

signal across the chemical synapse

and activate effector or back to 1

Neuronal RoadmapAs the neural system develops,

a distinctive network of interneuron connections is created. Neural circuit formation requires an intricate orchestration of ...

cell migration, axon guidance, dendritic growth, synaptic target selection, and synaptogenesis.Colón-Ramos et al. (p. 103) find that, in the nematode worm C. elegans, the supporting glial cells provide the requisite road map for making these [initial] connections.

... consistent with observations made in vertebrates and highlights the importance of glial cells in specifying precise neural connectivity.

Glia Promote Local SynaptogenesisThrough UNC-6 (Netrin) Signaling in C. elegans

DA Colón-Ramos et al. 2007. Science 318: 103 – 106.

Glial cells are important in neural development of functional connections

A cultured sensory neuron extending a growth conewith long thin filopodia, photo by Ken Balazovich

but then these initial connections are “sculpted” by experience;early on, many are lost;

things get simplified;then “sculpting” continues as learning

The picture can't be displayed.

Muscle length & velocity are monitored by muscle-spindle stretch receptors.

Activation of these receptors initiates the postural reflex: motor neurons of

synergists are activated (+) [to shorten]antagonists are inhibited (-).

[-FB system cycles; we wobble as we stand]

+ -

a

Note: these reflexes have evolved (are “designed”)to process incoming info very quicklyand initiate adaptive responsesvery quickly – without time consumingconscious deliberation and dithering.But – we can consciously control themand move our legs or suppress a blink.

A simple functional network:the Patellar postural reflex;

latent chicken pox emerge from dorsal root gangliato become shingles

http://en.wikipedia.org/wiki/ReflexAdult human reflexesBaby reflexes not seen in adults

Different reflexes mature or fadeat diff times and can be used to track neural development

All cells have a resting potential (ionic gradients) across the plasma membrane,but neurons have voltage-sensitive permeability (voltage-gated ion channels)

Membrane potentials are determined by (a) the ionic concentration differences across the membrane, and (b) the membrane's relative permeabilities to different ions.

Plasma membrane ATP-driven Na-K exchange pumps maintain intracellular sodium Na+ concentration low and potassium K+ high.

In almost all resting cells, the plasma membrane is much more permeable to K+ than to Na+;

the membrane potential is close to the K+ equilibrium potential, that is, the inside is negative relative to the outside. {about -70mV}

Water-soluable Ions cannot dissolve in thephospholipid plasma membrane;

they must either be pumped by membrane proteins ordiffuse through ion channels,

which are aqueous pores made of specific transmembrane protein molecules.

These molecular channels are selective for specific ions.

The Na+ & K+ gradients are created by an ATP-driven sodium-potassium pump and some back-flow diffusion through ion leak channels (more by K+).

Within neurons, graded potentials integrate information – inputs at dendritesand action potentials transmit decisions – outputs along axons

At excitatory synapse: an excitatory postsynaptic potential (EPSP) {depolarization}results when ligand-gated sodium channels are opened. (ex by glutamate)

At inhibitory synapse: an inhibitory postsynaptic potential (IPSP) {hyperpolarization}results when ligand-gated chloride channels are opened. (ex by glycine or GABA)

The postsynaptic cell's membrane potential is the result of temporal & spatial summation of the EPSPs and IPSPsat the many excitatory and inhibitory synapses on the cell.

This integrates information; a ‘decision’ at axon hillockcorresponds to whether depolarization > threshold ~ - 55mv;if yes, triggers +FB opening of voltage-gated Na+ & K+ cha

threshold ~ - 55mV

yes yes no

An action potential (AP; 2-5) is a self-propagating unidirectional waveof opening & closing of voltage-gated Na+ and then K+ ion channels,

In myelinated axons, APs

manifest saltatory {skippy} conduction;

allows small diameter axons to be fast;

Myelin is lost in multiple sclerosis (MS)

& “cross-talk” scrambles messages

Action potentials: +FB opening of voltage-gated Na+ then K+ channels (Fig 33.4)

Depolarization sends electrical field loops ahead and behind.

The unidirectionality results from hyperpolarization behind (5) but resting (1) in front.

Consider ‘crazy-bone’ initiation of AP in middle of axon – direction? APs: long-distance transmission of information w/o degradation (or processing);

information encoded by which axons are active & the frequency of APs in axon.

Most graded signals originate at chemical synapses on the dendritic tree

http

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.htm Pre-synaptic

reuptake transporter proteins remove neurotransmitter from cleft,turn the signal off.SSRIs like Prozac are Selective Serotonin Reuptake Inhibitors:serotonin signal ‘lasts longer.’Extasy (MDMA)is a serotonin reuptake inhibitor;Cocaine and ritalinare dopamine reuptake inhibitors

Prolonged hyper-stimulation of receptors often results in down-regulation of the number of receptors

- sets the stage for addiction.

The signal from a pre- to a postsynaptic neuron is a chemical neurotransmitterstored in presynaptic vesicles.

Depolarization of the axon terminalcauses the release of neurotransmitterinto the synaptic cleft.

The neurotransmitter diffuses across the cleft to receptors on the postsynaptic cell; opens ligand-gated ion channels.

Receptors move in and out of plasma membrane.

This Is How Your Brain Becomes Addicted to CaffeineStructurally, caffeine closely resembles adenosine

(which is a byproduct of cellular respiration). Caffeine can fit neatly into our brain cells’ receptors for adenosine,

effectively blocking them off. [an adenosine “receptor antagonist”]Normally, adenosine locks into these receptors

and produces a feeling of tiredness. In caffeine addicts, the brain increases the number of adenosine receptors,

which is the brain’s attempt to maintain equilibrium, with its adenosine receptors so regularly plugged (the brain also decreases the number of receptors for norepinephrine, a stimulant).[similar for drugs that increase dopamine levels – reduced # dopamine receptors]

This explains why regular coffee drinkers build up a tolerance over time -because you have more adenosine receptors, it takes more caffeine to block a significant proportion of them and achieve the desired effect.

This also explains why suddenly giving up caffeine can trigger withdrawal effects. … your brain is used to operating in one set of conditions

(with an inflated number of adenosine receptors, many blocked by caffeine). Suddenly, without the drug, [there is a big increase in adenosine effectiveness

resulting from lots of unblocked adenosine receptors - drowsy, headaches … .] The good news is that, compared to many drug addictions, the effects are

relatively short-term. You only need to get through about 7-12 days of symptoms without drinking any caffeine. During that period, your brain will naturally decrease the number of adenosine receptors on each cell,

• Each time you move a skeletal muscle it is because acetylcholine (Ach)has been released from a neuron to activate muscle

Alzheimer's Disease is associated with a 90% loss in the brain's production of Ach in the basal forebrain and hippocampus.

Nicotine mimics Ach at neuromuscular junction, autonomic & CNS.

• Human mood disorders (depressions) are treated with drugs that block the reuptake of serotonin (5-HT) into the presynaptic axon terminal, for example fluoxetine (Prozac) – this increases the postsynaptic activity of serotonin.

• Cocaine, opiates, nicotine and alcohol produce rewarding effects by promoting the release or inhibiting the presynaptic re-uptake of dopamine.{addiction is associated with reduced density of dopamine receptors }

Parkinson's Disease (PD) is accompanied by a selective destruction of dopamine neurons in the substantia nigra of the midbrain. PD is treated with L-dopa, a precursor of dopamine in the brain.[later: some things about dopamine, impulsivity, addiction and the placebo effect]

Schizophrenia is treated with drugs which block the binding of dopamineto its postsynaptic receptor sites.

•GLU (glutamate) is the main excitatory neurotransmitter in the brain. Its actions are mediated at two types of receptor (NMDA and AMPA) involved in memory formation

•GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the brain.

• Endorphins/Enkephalins are endogenous opiates found throughout the brain. Involved in pain reduction and pleasure (they enhance the effects of dopamine).

• Adenosine induces drowsiness & sleep [blocked by caffeine]

• NO increases vasodilation and blood flow [ breakdown inhibited by Viagara ]

p11 increases delivery of the serotonin 5-HT1B receptor

to the neuronal plasma membrane

where it can bind to serotonin;increases in p11 can be linked to

antidepressant effects

The study by Svenningsson et al. (Science 311, 77 2006) identifies an interaction between a brain protein called p11and a serotonin receptor (5-HT1B subtype)that has been previously associated with mood regulation.

... the authors show that a deficit of p11 is linked to depression

Perspectives NEUROSCIENCE: A New Molecule to Brighten the MoodTrevor Sharp Science 6 January 2006: Vol. 311. no. 5757, pp. 45 - 46A popular theory is that a breakdown in signaling

by the brain neurotransmitter serotonin (5-hydroxytryptamine; 5-HT)is critically involved in the symptoms of clinical depression,but the nature of this defect has proved elusive.

Health & ScienceStudy Sheds Light on How Depression Drugs Work

by Jon Hamilton

Antidepressants and electroconvulsive therapy (ECT) all caused an increase in the amount of p11 in the brains of mice.

So, it’s pretty convincing that p11 is associated with the main therapeutic action of antidepressant drugs.

http://www.nih.gov/news/pr/jan2006/nimh-06.htm

Editor's Summary 31 August 2006Dopamine by Choice

The brain messenger dopamine is traditionally known as the 'pleasure molecule',linked with our desire for food and sex, as well as drug and gambling addictions.

Using brain imaging, Pessiglione et al. (2006) scanned healthy human volunteers as they gambled for money after taking {dopamine altering} drugs ...

Volunteers with boosted dopamine became better gamblers[less impulsive, more willing to tolerate “short-term pain for long-term gain”](treated w/ l-DOPA a precursor of dopamine – used to treat Parkinson’s disease)than their dopamine-suppressed counterparts. (treated w/ haloperidol, which blocks dopamine receptors)

… confirming the critical role of dopamine in integrating reward information[anticipating future reward-pleasure … dopamine receptor blocking drugsare associated with serious impulse control disorders – gambling, addiction, crime]

Dopaminergic Network Differences in Human ImpulsivityJ.W. Buckholtz, et al. Science 30 July 2010 Vol. 329. no. 5991, p. 532

https://www.scientificamerican.com/article/dopamine-impulsive-addiction/Dopamine Determines Impulsive Behavior: Brain scans illuminate the internal connection among the neurotransmitter, impulsiveness & addiction.Katherine Harmon on July 29, 2010.A study by Buckholtz et al. showed that people who were more impulsive

have less active dopamine receptors in their midbrain but their brains release large quantities of the neurotransmitter when stimulated.

In the late nineteen-sixties,

Carolyn Weisz, a four-year-old with long brown hair,

was invited into a game room at the Bing Nursery School,

on the campus of Stanford University. …

A researcher then made Carolyn an offer:

she could either eat one marshmallow right away or,

if she was willing to wait a few minutes,

she could have two marshmallows when he returned. …

Then he left the room.

http://www.newyorker.com/reporting/2009/05/18/090518fa_fact_lehrer

Don’t!The secret of self-control. Jonah Lehrer MAY 18, 2009

Children who are able to

pass the marshmallow test

enjoy greater success

as adults.

[decades later, the children who couldn’t resist the 2nd treat]were more likely to have behavioral problems,

both in school and at home. They got lower S.A.T. scores.

They struggled in stressful situations, often had trouble paying

and found it difficult to maintain friendships.

The child who could wait fifteen minutes had an S.A.T. scthat was, on average, two hundred and ten points higher than that of the kid who could wait only thirty seconds. See: https://www.apa.org/helpcenter/willpower-gratification.pdf

See: http://www.youtube.com/watch?v=M0yhHKWUa0g

Dopaminergic Network Differences in Human ImpulsivityJ.W. Buckholtz, et al. Science 30 July 2010 Vol. 329. no. 5991, p. 532

EDUCATIONOne Size Does Not Fit All Pamela J. Hines

Some children, particularly those with a more fearful temperament, are more sensitive than others to the influence of parents, teachers, and environment.

Kegel et al. (2011) attempt to link this with a particular genetic polymorphism. Preschool children played a literacy-geared computer game

that delivered instruction and assignments to all participants, but differed in whether it delivered feedback about the children's choices.

A feature that distinguished the groups of children was whether they carried the long variant of the dopamine D4 receptor gene, which is associated with lower dopamine reception efficiency. [quality]

Children who carried the long [low affinity] polymorphism were more susceptible to the effects of feedback from the computer program.

[need approval – immediate external reward]They outperformed the control group when feedback guided their learning,

and they did worse than the control group when feedback was absent. In contrast, children with the short [high affinity] variant of the gene

seemed to be unruffled by the presence or absence of feedback. For education, just as for shoes, a good fit to the individual produces the best result.

genotype x environment interaction !!!

Differential Susceptibility in Early Literacy Instruction Through Computer Games: The Role of the Dopamine D4 Receptor Gene (DRD4). Kegel et al. Mind Brain & Educ. 5, 71 (2011).

Methylphenidate [ritalin] for ADHD: Mechanism of ActionFlavio Guzman, MD September 19, 2017The prefrontal cortex regulates attention, behavior and emotion. Deficits in prefrontal cortex functioning have been linked to ADHD symptoms:

poor impulse control, weak sustained attention and heightened distractibility. Norepinephrine (NE) and dopamine (DA) [catecholamines] are key neurotransmitters Methylphenidate [ritalin] inhibits the reuptake of dopamine and norepinephrine. This increases dopaminergic and noradrenergic activity in the prefrontal cortex and

may explain its efficacy in ADHD. [adderrall/amphetamine increases DA release]There is an inverted-U dose-response for catecholamines and prefrontal abilities.

In 2015, a meta-analysisof high quality clinical trials found that

therapeutic doses of amphetamine [adderall] and methylphenidate [ritalin] result in [brief] modest improvements in cognition, including working memory, episodic memory, and inhibitory control, in healthy adults without ADHD.

… using the drugs as study aids … does not actually improve GPA.Adverse effects include anxiety/nervousness, nausea, and insomnia.

https://www.nytimes.com/2013/02/10/magazine/why-can-some-kids-handle-pressure-while-others-fall-apart.html?src=me&ref=generalBy Po Bronson and Ashley Merryman Feb. 6, 2013The COMT gene [catechol-O-methyltransferase]carries the assembly code for an enzymethat clears dopamine from the prefrontal cortex, where we plan, make decisions, anticipate the future …There are two variants of the gene. One variant [Met158] builds enzymes that slowly remove dopamine. The other variant [Val158] builds enzymes that rapidly clear dopamine. We all carry the genes for one or the other, Stress floods the prefrontal cortex with dopamine –one COMT variant clears it slowly, the other rapidly.

Warriors versus worriers: the role of COMT gene variants.Stein et al. CNS Spectr. 2006 Oct;11(10):745-8.… individuals with Val158 [fast] alleles may have better performance when stressed, while individuals with Met158 alleles may have better performance when not stressed.

+ stress

Met158Val15

8

See: https://www.snpedia.com/index.php/rs4680 BUT note: large samples, small effect sizes-probably some truth to this, but explains only a little