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Introduction to Neurophysiology Glycine


Introduction to Neurophysiology Glycine

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									Introduction to Neurophysiology

1. Describe the architecture of a neuron with key organelles
       Neuron transmit information through electricity. Key parts are axons, dendrites,
       nodes of ranvier, schwann cells, myelin

2. List ionic composition of intra/extra cellular solutions of neurons.
         Low Na, Cl, and Ca and high K intracellularly
         Na – 15 in 150 out
         K – 150 in 5 out
         Cl – 9 in 125 out
         Ca - .1 in 2 out

3. Causes of Uneven ionic distribution
       Impermeable phospholipids membrane

4. Means by which ions cross membranes
      Ion channels, pumps, transporters, gap junctions

5. Importance of Ca as a intracellular messenger
     Neurotransmitter release is dependent on the level of presynaptic Ca. Elevated
       Ca can cause vesicular release, changes in gene expression, activation of K
       channels, cell differentiation, and motility. Too much Ca can cause neuronal death
     Regulate Ca through 1) ion channels letting it in. 2) sequestering in organelles
       (mito and ER) 3) binding proteins 4) expulsion pumps
Binds to calmodulin which activates other kinases

Resting Membrane Potential
1. Describe how uneven distribution of ions creates resting membrane potential
Neurons have a resting membrane potential of -70mV
Steady state requires 1) no movement of ions 2) osmotic balance 3) electrically neutral
     Uneven distribution of K - due to 1) membrane permeability 2) large intracellular
        organic anions 3) pumps going against concentration gradient
       The electrical gradient is stronger than the chemical gradient. when the Potassium
       leaves it creates a more negative intracellular environment. Since K is + it is now
       attracted to the negative intracellular environment. So you have more K inside.
     Continuous leak of Na in and K out
     Na/K pump restores gradient by pumping 3 Na out for every 2 K in

2. Use Nernst equation to fine equilibrium
58 log (ion out/ion out)
3. Contributioon of Na/K pump
        Restores the uneven distribution of the membrane gradient in regards to K. There
        is a continous leak of K out of the cell and Na in due to channel permeability. The
        pump brings in 3 K for every 2 Na is sends out, prevents depletion of K in and
        build up of Na

4. Structural features of K channels
     2 subunits each with 2 re-entrant pore loops
     Thus there are 4 pore loops per channel

5. K channel heterogeneity
        Come in the form of leak channels. Can be activated by depolarization, Ca, G
       proteins, second messengers. Many different genes encode for K channels

6. Understand Channelopathy
         Mutations that affect channel function giving rise to diseases. Ie: In K channels
       linked to cardiac arrhythmia and epilepsy

Voltage sensor – series of positively charged basic amino acids. Its on the fourth
membrane (s4) spanning out. When cell is depolarized the s4 moves causing the gate to
Ion Substitution – change extracellular content of an ion to see the effect on membrane
potential using an intracellular recording.

Generation of Action Potential – Voltage Gated Ion Channels
1. Difference between intracellular and extracellular recording techniques

2. Sequence of Ion Channel openings and closings during action potential
Resting – Na closed (m gated closed, h gate open), K closed (these are voltage gates –
there are leak channels for K and Na open)
Depolarization – Na open (both m and h gates)
Repolarization – Na closed ( m open, h closed), K open
Undershoot/Hyperpolarization – Na closed ( both m and h gates) , K open
Eventually K closes and the Na recovers from inactivation (with both gates closed)

3. Inactivation of Na channels
        Ball and chain blockage between pore loops 3 and 4 and the mouth of the pore.

4. Properties of Action Potentials
     Rapid wave of depolarization that leaves an after hyperpolarization as it travels
       along axons and dendrites.
     Membrane becomes permeable to Na to become depolarized.
      AP begins when neuron is depolarized to a voltage strong enough to activate Na
       channels (-50mv) for threshold. Regenerative one Na channels activates more Na
      All or none

5. Recogonize key features of the Na and ca channels that creates heterogeneity
     Na channel – alpha subunit is a single subunit with all four domains (each with 6
       transmembrane spanning segments), four voltage sensors, and four pore loops. S4
       spans out to open gate. Ball and chain blockage between pore loops 3 and 4 and
       the mouth of the pore.
     Ca channel – large alpha subunit that spans membrane 24 times. Intracellular N
       and C termini. Have a range of regulatory subunits (beta and alpha2-sigma) which
       can be mixed and matched. L type found on dendrites and cell bodies where they
       regulate gene expression through calmodulin. T type are on axon hillock to create
       AP. N and P/Q type are presynaptic and control Ca entry/neurotransmitter release
6. Understand Patch clamp and voltage clamp techniques

Refractory period – absolute between reaching threshold until 1/3 into repolarization –
No new APs. Relative is between this point and beginning of hyperpolarization – really
strong depolarization can cause AP
Passive vs Active membrane – Passive doesn’t create AP, active does

Iontropic Receptors
1. Excitatory and Inhibitory iontropic receptors and their agonists
     Excitatory – Glutamate (brain) – glutamate receptors, Acetylcholine – nicotinic
     Inhibitory – GABA – GABAa/b receptors, Glycine – glycine receptors

2. Why are receptors inhibitory or excitatory
Through EPSP and IPSP?

3. Causes of iontropic heterogeneity
     GABA – has different subunits alpah1-6, beta 1-3, gamma 1-3, sigma, episilon,
       rho 1-3 has a stoichiometry of 2alpha, 2beta, 1 gamma. Can also be alternatively
     NDMA – have NR1, NR2A-D stoichiometry 2 NR1 : 2NR2 , splicing
     AMPA – GlurR1-4 , RNA editing (glutamine to arginine now channel is
       impermeable to Ca) and splicing
     Kainate – GluR5-7, KA1 and KA2 – RNA editing, and splicing
4. Subtypes of Glutamate
     NDMA – coincidence detector for glutamate release simultaneously with
       depolarization. Peremeable to Ca but blocked by Mg – only strong depolarization
       can get through. For long term potentiation and memory
     AMPA – most common. GluR2-arg blocks Ca entry
     Kainate – we’re not sure what it does. Fabulous

5. Understand the terms activation, desensitization, deactivation
Desensitization – is the same as inactivation – receptors are refractory to activation by
agonist until agonist is washed off
Deactivation – closure of open ion channel after the unbinding of the agonist

Principles of Synaptic Transmission
1. Difference between electrical and chemical synapse
        Electric are gap junction, really fast, bad modulation
        Chemical – voltage gated ion channels, need presynaptic vesicles,
        neurotransmitter receptors. Many ways to modulate

2. Sequence for release of neurotransmitter
neurotransmitter synthesized and put in vesicles
    1. AP arrives
    2. Ca channels open
    3. Ca causes vesicles to fuse
    4. SNAP 25 on presynaptic terminal binds with synaptobrevin to bring vesicle close
       to membrane
    5. Synaptobrevin – on vesicle – brings close to membrane called priming
    6. Synaptotagamin- w/ Ca causes vesicle to release contents
    7. Molecules go into cleft
    8. Bound receptors active post synaptic cell
    9. Neurotransmitter breaks down. Vesicle membrane recycled

3. Why synaptic release is quantal
Each vesicle spills out neurotransmitter activiating a small group of postsynaptic
transmitters. Need many quanta to activate a postsynaptic cell

4. Class of neurotransmitter, where its synthesized, how they are removed
     Acetylcholine – synth- presynaptic, removed ACTHerase
     Adregenic – synth- presynaptic , removed – reuptake by terminal and transporters
     Amino acid – synth – presynaptic, removed – reuptake by terminal and glial cells
        and by specific transporters
      Peptide – synth – cell bodies transported through axon, removed by peptidases
       and diffusion away from synapse

5. Presynaptic and Postsynaptic modulation
Presynaptic – regulation and release of neurotransmitters
Postsynaptic – how many receptors are sequestered
Presynaptic – Muscarinic inhibition– opens K channels harder to depolarize, Nicotinic
excitation- depolarizes terminal to Ca so there is direct flow into terminal

6. Long Term Potentiation
NDMAR – up Ca – up Protein Kinase and calmodulin Kinase which can
a) phosphorlate AMPAR for short term – increases AMPAR and NDMR at synapse
b) synthesize PKMZ (continoulsy active once initiated) which will phosphorlate AMPAR
for long term potentiation through protein synthesis – which will then increase ion flow
thorugh activated AMPARS and increase number of NDMAs at synapse

Sensory Systems
Exteroceptors – touch, pressure, pain, hearing , vision
       Noncapsulated – free nerve ending (pain), merkels (crude touch), hair (touch)
       Capsulated – Meissners (fine touch), Pacinian (vibration, Ruffini (stretch)
Interocepters – for visceral sensation ie stomach distension
Propiocepters – muscle spindles, golgi tendon
Rapid Adaptation- time course of afferent AP – Pacinian, Meissener, Hair
Slow Adaptation – time course of afferent AP – Merkels, Joint receptors
Muscle Spindles – 1a- respond to change in muscle length - reflex
Golgi Tendons – 1b - respond to change in muscle tension - reflex
Mechanoreceptors – respond to mechanical energy
Noiciceptors – free nerve endings for pain
Thermoreceptors – for temperatures
Demylenation – can causes blocked or slowed nerve conduction
Parathesia – pins and needles from excessive activity in sensory pathways – usually
some series of nerve impulses at lower threshold or enhanced excitability nervous system
Orthrodomic – normal direction
Antidromic – not normal direction
Clinical test of nerve conduction. Compound vs. single AP
       Compound – not all or none, more stimulus , more fibers become activated
Group I – A alpha – velocity 100, Diameter 16u, muscle length, tendon tension
Group II – A beta velocity 50, d- 8 u – touch, pressure, vibration
Group III A delta velocity – 25, d-4u – fast pain, temperature, crude touch
Group IV – C velocity 1, d 1u slow pain, temperature crude touch
Receptive field – each neuron has a an area on skin where stimuli elicit a change in
       excitation level
Slow pain – conducted in A – delta - pricking
Fast pain – conduced in C – burning or aching
Substance P – released from A delta and C fibers. Opiates inhibit transmission of these
       to spinothalamic tract
Referred pain- pain due to the convergence of peripheral and visceral fibers
Projected pain – from neural pathway but expressed from area innervated
Gating – touching or shaking to decrease pain due to stimulation of Group II, inhibits
       pain pathway
TENS – activate Group II to produce gating
Descending analgesic – inhibit noiceptor from midbrain inhibits spinothalamic tract
Nonsteroidal/anti inflamm drugs – ie asprin reduce prostaglandin- which sensitizes
nerve receptors. Local anesthetics block Ap conduction by inhibiting Na intracellular
(TTX extra). Narcotic – bind with opiate – reduce reticular acitivty. Antidepressants
block reuptake or serotonin receptors
Non Drug – hypnosis or placebo, focusing attention, gating, psychological support

Auditory and Vestibular Function
Frequency – cycles/sec = Hz audible sound from 20 – 20,000 Hz speaking 150 – 250
Amplitude – Decibels – normal convo is 50, discomfort at 120
Air Conduction – through external ear and ossicles
Functions of Middle Ear – Amplification 15 to 1 from tympanic membrane to stapes in
       oval window. Protection with middle ear reflexes – reduces transmission of
       vibration and equalization of pressure through Eustachian tube.
Bone Conduction – through skull directly to cochlea bypassing air pathway
Cochlea and sound perception of frequencies – traveling waves through basilar
       membrane. High freq by base of cochlea near middle ear, near apex (helicotrema)
       from low freq. Sound ID is based on where on the basilar plate is activated by the
Hair cells create nerve impulses – Pivoting of hair bundles in one direction increase ion
       channel opening – tips sterocilia over to the right and opens transduction canals
       sending in K to depolarize the hair. Supply most info to CN VIII which increase
       nerve impulse freq to those fibers.
Frequency and tuning curves – sound intensity plotted vs sound frequency to show the
       best freq that nerve fiber is for sound sensitivity. plot shows full range of sound
Hearing loss – Auditory(conduction) vs. Nerve lesion –
       Conduction loss due impaired conduction through external or middle ear
       Nerve Deafness due to impaired hair cells, auditory nerve, or auditory pathways.
       Use audiometry to distinguish – conduction will have only a little deviation for
       the impaired body part – nerve will have an entirely shifted line
Brain Stem auditory response – average brain electrical response to repeated stimuli.
       First wave Is auditory nerve activity next wave is higher up brain levels.
Semiciruclar canal stimuli- angular acceleration
Utricle stimuli – linear acceleration and gravity leads to reflex righting of head,
       perception of motion and space orientation
Vestibulocular reflex – automatic movement of eyes opposite to movement of the head
Nystagamus – normal back and forth eye movement due to rotation
Caloric Test – cool water in the ear causes endolymp currents similar to rotation –
       allows you to check for left and right vestibular systems separately.

Physiology of Vision
Eye focusing and refraction – anterior part bends light – measured in diopters
       Refractive errors – myopia – eye is too long, focuses anterior to retina,
       Hyperopia – too short between cornea and retina nearby objects can’t focus on r
       Astigmatism – curvature and refractive power are greater in one plane
Reabsorbtion of aqueous humor –
Presybyopia – loss of accommodation
Accomodation – lens becoming more convex (by para fibers from CN III) also papillary
Development of Glaucoma – excessive pressure from blockage of reabsorption of
       aqueous humor
Pupil size control – iris muscle which is innervated by para fibers from CN III which
       cause constriction and sympathetic fibers causing dilation
Pupillary light reflex – due to light -
Retinal cells to light – fixation point at the macula, blind spot at the optic disc. Rods and
       Cones are retinal photoreceptors that absorb light and hyperpolarize. Ganglion
       cells that depolarize increase rate of nerve impulses from optic nerve.
       Na channels open in the dark releasing neurotransmitters. Light causes some Na
       channels to closes hyperpolarizing and reducing neurotransmitter release.
Visual acuity – ability to see small details. Can do snellen test (the eye chart). Normal is
       20 feet can read 1/60 of a degree
Rods – found in periphery of retina. More sensitive to dim light and adapt after 20
       minutes (first component of adaptation is from cones). have rhodopsin –
       composed of retienene, vit. A, and opsin. Light changes Na channels. Retiene
       changes in light and then is recycled
Cones – cones are more central, concentrated in fovea. Do blue-violet, green, yellow-red.
       Have much better visual acuity, greates near fixation point in fovea
Saccadic Eye movement – jump like eye movement from frontal eye field. Occur when
       scanning, reading, moves eye to object of interest of focus it on fovea. Superior
       colliculus helps out.

Motor Function
Muscle stretch reflex – increased muscle length > Group Ia fibers > alpha motor
neurons > efferent fibers on skeletal muscle.
Gamma efferents - control sensitivity
Supraspinal control - governs strength of reflex
Phasic contraction – brief
Tonic contraction – longer lasting
Spinal Reflex – increased tension leads to inhibition of motor neurons to the muscle and
        causes relaxation
Jaw Jerk – CN 5
Biceps reflex – C5 and C6
Triceps reflex – C6 and C7
Knee Jerk – L2, L3, L4
Ankle jerk reflex – S1
Golgi Tendon Reflex – Ib fibers, tension causes reflex, involves two synapses, and an
        inhibitory interneuron,
Normal muscle tone -
Flexor withdrawal reflex – Pain through A delta and C fibers to interneurons to LMN to
        flexor muscles. Noiciceptors create flexor withdrawal. Can have crossed
        extension to support the withdrawl
UMN – voluntary movement and inhibition to spinal reflexes. Brain stem motor areas
give rise to descending tracts (extracorticospinal tracts) outside of the corticospinal tracts.
LMN – each innervates a motor unit consisting of anywhere from 4 to 100 muscle fibers
Lower motor neuron disorder – interrupt stretch reflex causing flaccidity, hyporeflexia
Upper motor neuron disorder– hyperactive DTR, clonus, spasticity, disorder release
        stretch reflexes from inhibition
Spasticity – muscle rigidity
Flaccidity – muscle overly relaxed
Clonus – pendulum like response to a reflex
Muscle contraction – AP arrive, depolarization along T tubules, release of Ca from t
        terminal cisterns to Sarcoplasmic reticulum to thick and thin filaments. Ca binds
        to troponin – uncovers myosin head > cross links between actin and myosin =
Muscle twitch – AP in LMN causes a brief contraction that starts about 2 msec after
        depolarization starts
Slow motor unit – innervated by small slower conducting LMN – for sustained, strong,
        gross movement, with twitch durations up to 100ms
Fast motor unit – innervated by fast larger LMN for fine rapid precise movements with
        twitches lsting around 7.5 ms
Cerebellum control – coordinate timing of movement for rapidly changing or skilled
        movements. Also does planning and initiating voluntary movements. Cerebellum
        dysfunction can cause ataxia, overshooting, intention tremor
Basal Ganglia – influence over motor cortex via the thalamus. Plan and execute smooth
        movements. Disorders can cause parkinsons (too little movement) Chorea,
        athetosis, hemiballismus (too much movement)
Autonomic Nervous System

Sympathetic nervous system – fight or flight, rapid use of energy, HR up and
        vasoconstriction of blood vessesl to GI, more blood to active muscle, dilation of
        pupils and bronchioles. From the thoracic and lumbar segments of the spinal cord
        short preganglionic fibers long postganglionic
Parasympathetic nervous system – rest and digest, energy to be stored, HR down, atrial
        contractility down, digestive activity up, pupils constricted. From the cranial
        nerves and sacral segements of the cord
        long preganglion, short postganglionic
Nicotinic – ligand-gated ion channels found in postganglionic cells in both S and PS and
        skeletal muscle. ACH binds, cation channels open and cell is depolarized
Muscarinic – are G protein coupled found in effector cells activated by PS fibers, effector
        cells by S cholinergic fibers. Lead to second messengers
Alpha – vasoconstriction of arterioles and papillary constriction
Beta – increased heart rate and dilated bronchioles
Agonist – enhance or mimic the response to a neurotransmitter – ie: salbutamol/albuterols
is a beta 2 agonist that causes dilated of the bronchial s. muscle
Antagonist – block the response to a neurotransmitter ie: atropine – muscarinic – dilates
pupil, treats acute angle glaucoma,

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