Neurophysiology, Neurotransmitters Neurophysiology, Neurotransmitters and the Nervous Systemand the Nervous System

The NeuronThe Neuron

The nervous system is made of nerve cells or neurons and glial cells. Glial cells are not excitable and provide metabolic and physical support for the neurons. 90% of the cells are glial cells. Neurons are excitable and control behavior

NeuronNeuron

Resting potentialResting potential

Resting potentialResting potential

There is a potential difference between the inside and outside of as membrane. The inside is about -70 mv relative to the outside.

Resting PotentialResting PotentialThe resting potential is caused by an uneven distribution of ions (electrically charged molecules) of potassium (K+) and sodium (Na+) and chloride (Cl-).

This is caused by Na+/K+ ion pumps that move 3 Na+ ions out of the cell for every 2 K+ ions it moves in.

Therefore there are more +ions outside the cell than inside and the inside is negatively charged with respect to the outside

Ion pumpIon pump

Resting potentialResting potential

An ion channel is a combination of large protein molecules that cross the membrane and allow specific ions to pass through at a specific rate,

These allow enough leakage of ions to mostly neutralize the effect of the ion pump, but

Ion channelsIon channels

Resting potentialResting potential

Forces maintaining the resting potentialForces maintaining the resting potentialDiffusion pressure – molecules want to move Diffusion pressure – molecules want to move

from areas of high concentration to areas of low from areas of high concentration to areas of low concentration.concentration.

Electrostatic charge – ions with like charge are Electrostatic charge – ions with like charge are repelled and ions with a different charge are repelled and ions with a different charge are attracted.attracted.

Operation of ion pumps and ion channels. Operation of ion pumps and ion channels.

Action potentialAction potential

Anything that alters the functioning of the ion Anything that alters the functioning of the ion channels can change the resting potential.channels can change the resting potential.

If changes cause the resting potential to be If changes cause the resting potential to be reduced, this is called reduced, this is called depolarization.depolarization.

If the change causes an increase in the resting If the change causes an increase in the resting potential, this is caused potential, this is caused hyperpolarizationhyperpolarization..

Action PotentialAction Potential

We can insert an electrode across a We can insert an electrode across a membrane and cause depolarization, i.e., membrane and cause depolarization, i.e., we can depolarize the cell.we can depolarize the cell.

If we reduce the resting potential past a If we reduce the resting potential past a thresholdthreshold, the resting potential breaks , the resting potential breaks down.down.

Action potentialAction potentialVoltage gated ion channels open and let Na+ into the cell. Voltage gated ion channels open and let Na+ into the cell. They are driven into the cell because of diffusion gradient They are driven into the cell because of diffusion gradient and electrostatic charge.and electrostatic charge.

This causes the resting potential to reverse, i.e., the inside This causes the resting potential to reverse, i.e., the inside the cell becomes positive.the cell becomes positive.

Now the Na+ ion channels close and the K+ channels open Now the Na+ ion channels close and the K+ channels open and the K+ ions are driven out of the cell because of their and the K+ ions are driven out of the cell because of their concentration gradient and electrostatic charge. concentration gradient and electrostatic charge.

Finally the K+ channels close and the ion pumps kick in Finally the K+ channels close and the ion pumps kick in and the resting potential returns to normal.and the resting potential returns to normal.

Action potentialAction potential

All or None LawAll or None Law

Action potentials when they occur are Action potentials when they occur are always the same. always the same.

Once the process is initiated, it must run its Once the process is initiated, it must run its course and nothing can stop it or change itcourse and nothing can stop it or change it

Transmission of action potentials along Transmission of action potentials along a membranea membrane

When an action potential occurs at one When an action potential occurs at one place on the membrane of an axon, the place on the membrane of an axon, the surrounding membrane is depolarized past surrounding membrane is depolarized past threshold causing an action potential. This threshold causing an action potential. This depolarizes the neighboring membrane, depolarizes the neighboring membrane, etc. etc.

Action potentials sweep across a Action potentials sweep across a membrane as fast as 100m/secmembrane as fast as 100m/sec

Transmission of action potentials along Transmission of action potentials along a membranea membrane

Postsynaptic potentialsPostsynaptic potentials

The membranes of dendrites and cell The membranes of dendrites and cell bodies do not have action potentials. bodies do not have action potentials. Instead, any depolarizing stimulus causes Instead, any depolarizing stimulus causes a post synaptic potential (PSP) which a post synaptic potential (PSP) which spreads out across the membrane. The spreads out across the membrane. The depolarization is weaker the further it gets depolarization is weaker the further it gets from the stimulus. When the stimulus is from the stimulus. When the stimulus is turned off, the PSP disappears.turned off, the PSP disappears.

Postsynaptic potentialsPostsynaptic potentials

Postsynaptic potentials can either be Postsynaptic potentials can either be excitatory (depolarization) or inhibitory.excitatory (depolarization) or inhibitory.

Excitatory and inhibitory potentials can Excitatory and inhibitory potentials can summate both in time (summate both in time (temporal temporal summationsummation) and across the membrane ) and across the membrane ((spatial summationspatial summation) .) .

The net effect of summation is reflected at The net effect of summation is reflected at the axon hillock where action potentials are the axon hillock where action potentials are generated.generated.

The synapseThe synapse

Normally, cell bodies are stimulated by Normally, cell bodies are stimulated by either byeither bystimuli in the environment, e.g. sensory cells stimuli in the environment, e.g. sensory cells

like the rods and cones in the eye, orlike the rods and cones in the eye, orConnections from other nerve cells, i.e., Connections from other nerve cells, i.e.,

synapsessynapses

The SynapseThe Synapse

The SynapseThe Synapse

SynapseSynapse

Any neuron can have thousands of synapses on it

SynapseSynapse

When an action potential arrives at the When an action potential arrives at the terminal terminal boutonbouton, it causes Ca++ channels to open., it causes Ca++ channels to open.

This causes the vesicles to move to the membrane This causes the vesicles to move to the membrane and release a chemical called a and release a chemical called a neurotransmitterneurotransmitter to be released into the synaptic cleft.to be released into the synaptic cleft.

The neurotransmitter diffuses across the cleft and The neurotransmitter diffuses across the cleft and activates receptors on the postsynaptic membrane activates receptors on the postsynaptic membrane which cause changes on the resting potential by which cause changes on the resting potential by altering the functioning of ion channels. altering the functioning of ion channels.

ProteinsProteins

Ion pumps, ion channels, etc., are large Ion pumps, ion channels, etc., are large molecules of protein.molecules of protein.

Proteins are long strings of amino acids that can Proteins are long strings of amino acids that can fold into many three dimensional shapes. The fold into many three dimensional shapes. The same protein can have different configurations, same protein can have different configurations, i.e., they can change shape. i.e., they can change shape.

Receptors are protein molecules that change Receptors are protein molecules that change shape (are activated) by neurotransmitter shape (are activated) by neurotransmitter molecules with a particular shape.molecules with a particular shape.

ReceptorsReceptors

Receptor sites can be Receptor sites can be part of an ion channel part of an ion channel and when the receptor and when the receptor site is occupied by a site is occupied by a neurotransmitter, the neurotransmitter, the ion channel opension channel opens

Post synaptic potentialPost synaptic potential

The change in the resting potential caused by the The change in the resting potential caused by the activation of a receptor site is called the post activation of a receptor site is called the post synaptic potential (PSP). synaptic potential (PSP).

IPSP – when the change causes IPSP – when the change causes hyperpolarization or makes the cell harder to fire, hyperpolarization or makes the cell harder to fire, this is called an inhibitory post synaptic potential.this is called an inhibitory post synaptic potential.

EPSP – when the change causes depolarization, EPSP – when the change causes depolarization, this is called an excitatory post synaptic potential.this is called an excitatory post synaptic potential.

Post synaptic potentialPost synaptic potential

The excitation and inhibition caused by all The excitation and inhibition caused by all the active synapses on the dendrites and cell the active synapses on the dendrites and cell body are summed and the net effect is body are summed and the net effect is reflected in the rate at which the axon hillock reflected in the rate at which the axon hillock generates action potentialsgenerates action potentials

SummationSummation

Terminating synaptic actionTerminating synaptic action

Once the neurotransmitter is released into Once the neurotransmitter is released into the cleft, there must be a means by which the cleft, there must be a means by which its activity is terminated. This can be its activity is terminated. This can be accomplished two waysaccomplished two waysThe neurotransmitter can be destroyed by an The neurotransmitter can be destroyed by an

enzyme in the cleftenzyme in the cleftThe neurotransmitter can be reabsorbed back The neurotransmitter can be reabsorbed back

into the bouton (reuptake).into the bouton (reuptake).

Second messengerSecond messenger

The neurotransmitter causes the release of a molecule inside the cell which activates an ion channel and causes it to open

Second messenger cascadeSecond messenger cascade

Second messenger cascadeSecond messenger cascade

Second messenger molecules can activate a Second messenger molecules can activate a kinasekinase which lasts for minutes and hours. which lasts for minutes and hours.

Kinases can activate Kinases can activate transcription factorstranscription factors (CREB and c-fos) which alter the expression of (CREB and c-fos) which alter the expression of genes.genes.

Genes carry the codes for the creation of proteins Genes carry the codes for the creation of proteins including ion channels and receptor sites and this including ion channels and receptor sites and this can cause permanent changes in synaptic can cause permanent changes in synaptic function.function.

autoreceptorsautoreceptors

The membrane of the presynaptic cell has The membrane of the presynaptic cell has many receptor sites which detect the many receptor sites which detect the neurotransmitter. This is a feedback neurotransmitter. This is a feedback system which regulated the amount of system which regulated the amount of neurotransmitter released into the cleftneurotransmitter released into the cleft

Other signaling between neuronsOther signaling between neurons

Neuromodulators are chemicals that can alter the effect of a Neuromodulators are chemicals that can alter the effect of a neurotransmitter.neurotransmitter.

Sometimes the postsynaptic membrane releases molecules Sometimes the postsynaptic membrane releases molecules that affect the presynaptic membrane. that affect the presynaptic membrane.

DSE- depolarization-induced suppression of DSE- depolarization-induced suppression of excitationexcitation DSI – depolarization-induced suppression of inhibition.DSI – depolarization-induced suppression of inhibition.

Axo-axonal synapses: axons may also have synapsesAxo-axonal synapses: axons may also have synapses

Neurotransmitters

Acetylcholine (Ach)

Biogenic amines (monoamines)catecholamines:

Norepinephrine (NE)Dopamine (DA)Epinephrine (E) (adrenaline)

indoleamineSerotonin (5-HT, 5-hydroxytryptamine)

Amino acids:GABAGlycineGlutamateProline

PeptidesSubstance PSomatostatinVasopressinGrowth hormoneProlactinInsulinOpiate-like transmitters

EnkephalinsEndorphins

carbon monoxide

nitric oxide

Many hormones are neurotransmitters. Both have the same function: chemical signalling over distances.

Neurohormones

Substances that act at neuron receptor sites, but are not specific to an individual synapse.

May be released far from the synapse.Act as a neuromodulator (modify the

activity of a neurotransmitter)

Dale’s Law

A single neuron always produces the same transmitter at every one of its synapses.

It is now known that the law is not always right.

Drugs mostly act on the nervous system by interacting with neurotransmission,They may:act on receptor sites and cause the same effect as a transmitter: agonismblock a receptor site: antagonismdecreasing activity of enzymes that destroy a transmitterblock reuptake mechanismsblocking ion channelsaltering release of transmitteraltering the action of neurohormones

Synapses that use NE are nor adrenergic (remember, adrenaline is another word for epinephrine)

DA are dopaminergic 5-HT are serotonergic ACh are cholinergic etc

Acetylcholine:

Broken down by AchE (acetylcholinesterase)

Receptors: nicotinic and muscarinic

Stimulated Blocked Function

nicotinicnicotine curare Voluntary muscle control

(neuromuscular junctions)

muscarinic muscarine atropine Involuntary muscle control

botox and nerve gasses

Biogenic aminesSerotonin, Dopamine Norepinephrine and

EpinephrineBroken down by MAO and COMTReabsorbed by transporter mechanisms

Influenced by amphetamines and cocaine and SSRIs and SNRIs

E and NE receptor sites alpha (α)and Beta (β) with subtypes 1 and 2DA has 6 receptor subtypes D1 and D2....D6 with sub sub types a b c, etcSerotonin has 4 main receptor subtypes with sub sub types a b c etc.

GABAGABA

Universally inhibitory transmitterUniversally inhibitory transmitterOpens a Chloride ion channel which stabilizes the Opens a Chloride ion channel which stabilizes the

membrane and makes it harder to depolarizemembrane and makes it harder to depolarizeDrugs like benzodiazepines enhance the ability of GABA Drugs like benzodiazepines enhance the ability of GABA

to open the ion channel. to open the ion channel. There are two types of GABA receptors; GABAA and There are two types of GABA receptors; GABAA and

GABAB. GABAB. There are many different subtypes of GABAA receptors There are many different subtypes of GABAA receptors

which control different functions.which control different functions.GABAB receptors are less common and use a second GABAB receptors are less common and use a second

messengermessenger

GABAGABA

Glutamateexcitatory transmitterNMDA receptor open ion channel and lets +ions

into the cellthe channels can be blocked by alcohol, solvents

and some hallucinogens

Peptidesopioid type peptides

enkephalins (5 amino acids)endorphines (16 to 30 amino acids)

Receptor subtypes mu, kappa and delta

The Nervous System

Central Nervous System (CNS)brain and spinal cord

Peripheral Nervous system (PNS)everything else

somatic NSconscious senses and voluntary muscles transmitter is Ach and uses nicotinic

receptors

autonomic NS unconscious senses and involuntary

musclestransmitter is Ach with muscarinic

receptors.

Autonomic NSsympathetic and parasympathetic divisions

Parasympatheticalways active,controls daily vegetative functions Ach major transmittersome drugs have “anticholinergic” side effects,

e.g dry mouth and blurry vision

Sympatheticactive at times of fear and angerfight - flight responseepinephrine (E) major transmitter

CNSspinal cord

Brain100 billion neurons. each has 100 synapses on

other neurons and receives 10,000 synapses from other neurons

Spinal cordSpinal cord

BrainBrain

Medulla:

Autonomic control centre:

Respiratory centre controls breathing

Vomiting centre

Cardiac functions

Very sensitive to “depressant” drugs like alcohol, opioids and barbiturates

Brain damage caused by drug overdose is a result of lack of oxygen

RAS and Raphé System

RAS ‑ arousal- many interconnected centres- diffuse projection to cortex and higher centres

Raphé System- many independent centres- serotonin- medial forebrain bundle projects forward

‑ sleep ‑ mood

Locus Coeruleus

mood: fear, panic, angerprimarily NE, (50 to 75% NE neurons in the brain)stimulated by monoaminesinhibited by GABAactive during panic attack

Cerebellum:

Coordination of motor control

Receives input from the motor areas of the cortex and the muscles and coordinates smooth muscle movement.

Coordinates eye movements.

Basal Ganglia:Input side:striatum – caudate nucleus and putamen

- input from thalamus and cortexOutput side:globus palladus - output side with feedback to thalamus“Motor loop”

coordination of motor control- DA input from substantia nigra- DA receptors- DA deficiency ‑ Parkinsons Disease- extrapyramidal motor system

Periaquiductal gray:

pain control - mu receptors and morphine-like transmitters punishment system

Limbic system:

hypothalamus - eating and drinking control

medial forebrain bundle‑‑‑ reinforcement (pleasure?) centres

mesolimbic system (DA)ventral tegmental area (VTA, mu receptors)nucleus accumbens

hippocampus - learning and memory

amygdala and septum - serotonergic input from the Raphé system Aggression and emotion Inhibited by GABA

CortexCortex

Cortex

sensory input areasmotor control output areaslanguagememory and thinking

glutamate ‑ excitatory transmitterGABA ‑ inhibitory transmitter

Frontal and prefrontal cortexFrontal and prefrontal cortexFrontal and prefrontal cortex: monitors relationship between cues and reinforces (outcomes of behavior), inhibition of behavior and the expression of emotion.

Orbitofrontal cortex: learning and behavior control

Prefrontal cortex: working memory, attention, decision making, reasoning, planning and judgment.

Dorsolateral prefrontal cortex: maintenance of attention and manipulation

Anderior cingulate cortex: attention, response selection, response suppression, drug seeking and craving.

DevelopmentDevelopment

Formation of neurons

Migration

Attachment and axon projection

Growth cone

Development and teratologyDevelopment and teratology

Extension of axons is controlled by trophic factors, chemical signals that guide it to its target.

These signals can be easily disrupted by drugs and cause incorrect wiring of the CNS

Eg: fetal; alcohol syndrome – only 4 layers rather than the normal 6 in the cortex.

Teratology: disruption of normal anatomical development, e.g thalidomide

Functional teratology: a disruption of normal behavioral development.