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The operation of the nervous system is entirely dependant on two key characteristics of every neural cell

-neurons generate a signal -neurons have precise anatomy and precise connectivity

Neurons are specialized for the reception, transformation and transmission of electrical signals.

-signal is a deviation from the normal electrical state also known as the resting membrane potential

At rest there is a small difference in electrical voltage between the inside and outside of a cell this is called the membrane potential (typically the voltage difference is less than 90 thousandths of a volt -by convention the voltage of the ECF is defines as 0

For Normal cells RMP ranges from -40 to -90

-major ions ->K+ Na+ Ca+ Cl-

Properties of the PM phospholipid bilayer -impermeable to ions acts a capacitor -channel proteins - all exhibit selective ion permeability

-gated channels -non-gated channels (leak channels) <-responsible for RMP

There are 2 main forces which bring about the RMP 1) Diffusional force 2) Electrical force

at equilibrium potential no net movement of ions

Nernst equation

Eion = RT/zF ln [ion]o / [ion]i

R= gas constant T = Temp (K) Z= valance F = Faraday's constant

Eion = 60 log base 10 [ion]o/[ion]i

ion concentrations

ion extracellular conc intracellular conc potential K+ 4mM 130mM -92mV Na+ 140mM 15mM 59mV Cl- 116mM 5mM -83mV Ca++ 2.5mM .0001mM 134mV

EM = 61 log base 10 Pna[Na]o + Pk[K]o + Pcl[Cl]i / Pna[Na]i + Pk[K]i + Pcl[Cl]o

P = Permeability

K and Na are the two major players

->membrane is 10x more permeabile to K than to Na

Roles of Na+/K+ pump - maintenance of ion gradient -very few ions actually move through leak channels to establish the RMP

0mV -> -80mV -> 100mM -> 99.999999mM

a neuron may generate up to 1000 AP each second over time that does result in changes in ionic concentraions The concentration gradient of Na and K are established embryologically and maintained by the actions of the Na/K exchange pump 3 Na out 2 K in ... Moving ions against the concentration gradient requires ATP and neurons are normally so electrically active that this pump is responsible for consumption of over 50%of the brain's total ATP

At rest tghe membrane is polarized

depolarized - inside of neuron becomes more + relative to RMP hyperpolarize - inside of neuron becomes more - relative to RMP repolarize return to RMP

2 types of electrical signals that occur in neurons 1) graded potentials (passive) 2) action potentials (active)

both signal types are a deviation of the resting membrane potential -all channels in membrane potential result from opening of gated ion channels

3 different kinds of gated channels -ligand gated -voltage gated -sensory stimulus gated channels -mechanical -thermal

opening of gated channels changes the membrane permeability and subsequently changes the membrane channel

-hyperpolarizing (opening Cl- or K+ channels) -depolarizing (opening Na or Ca)

neurons are polarized cells and neuronal signalling is unidirectional

cell body + axon + few synapeses

graded potentials happen in the dendites to the start of the axon

possibility of generating an ap ap -- > synapse

how graded potentials can influence the AP

graded potentials -all sensory inputs and interneuron synaptic inputs result in graded potentials -can occur anywhere there is a synapse -> most common in dendrites - have a variable amplitude -travel short distances -gp do not directly cause NT release

there are 2 categories of graded potentials defined by their affect on RMP 1) EPSPs (excitatory postsynaptic potential) depolarizations 2) IPSPs (inhibitory postsynaptic potential) hyperpolarization

-graded potentials result from a change in ion permeability due to opening of ligand or mechanically gated channels

graded potential decays with distance

there is a time delay in reaching maximum voltage change (defined by a time constant there is also a time delay to return to RMP -temporaral summation

Action potential Graded Potential All or none variable always depolarizing dep or hyper only intiated at axon hillock anywhere postsynaptically do not weaken w/ distance decay

the voltage change at which sufficient voltage gated Na channels open to initiate an AP is called the threshold potential (~+15mV above RMP --> ~-55) subthreshold depolarization never produce AP superthreshold depolarizations can result in AP

the electrical characteristics of the AP result from 2 channels -voltage gated Na channel 2 gates activation gate and inactivation gate the channel can exist in 3 configuartions

resting state at RMP


inactivated state .5ms delay

voltage gated K channel 1 gate opens slowly in response to depolarization open until repolarization to RMP

how might Na channel be clinically important

  • primary target for local anesthetics-> bind to inactivation gate -> inactive state -> pain neurons

AP consists of 3 phases depolarization voltage Na channel influx of Na rapid depolarization (.5) ends when inactivation of Na channels (peak of depolarization) repolarization voltage gated K channels open towards RMP hyperpolarization voltage gated K channels start closing at RMP but are slow to close

absolute refractoryperiod all of depolarization phase and most of the repolarization phase ends when na channel converts from inactive state and -50mV

relative refractory period lasts until the end of the hyperpolarization phase ap can be generated by sufficiently strong excitatory stimuli (large # of EPSPs)

clinical significance of K channel alteration in K+ channel closes early neurons fail to hyperpolarize shorter refactive period neurons are hyperexcitable more active than normal -> hyperexcitablility

AP Propagation initated at axon hillock by depolarization past threshold subsequent depolarization of adjacent part of membrane >> past threshold density of voltage gated channels in

AP conductio speed is determined by 2 factors diameter and degree of mylenation 1) larger axon diameter = faster AP conduction speed smallest unmylinated axons in humans are .2 micrometers in diameter and conduct at .5 m/s largest unmylinated are 1.5microm in diameter and conduct at 2.5 m/s -invertebrates use large diameter axons for rapid escape reflexes

  • squid giant axon 25m/s

2)mylenation dramatically increases conduction for 2 reasons

a) increase in membrane resistance b) ion diffustion is restricted to the Nodes of Ranvier

20 microm diameter axon + myelination -> 120 m/s

Clinical signification loss of myelin

Multiple sclerosis affects CND myelin (oligodendricites can occur anywhere in CNS white matter Most common symptoms

1)Pins and Needles (paraesthesia) in the limbs spinal cord white tracts

2) Scotoma (patch of blindness) usually in one eye looks like a plaque in path sections plaque formed in the optic nerve

3) clumsiness -> gait disturbance plaque in cerebellum

MS is characterized by periods of relapse and remission with chronic accumulation of neurologic symptoms. These are worsened by incereases in body temperature. Newer tratments include use of B-interferon

Guille Barre Syndrome autoimmune disease acute inflammatory polyradiculorneuropathy

autoimmune attacks on myelin in the pns mainly demyleinationg axons of motor nerve

guille-barre -> progressive weakness *ascending* in the body

anatomy of the synapse -axons terminate in small swllings called synaptic boutons, terminal boutons or axon terminals -presynaptic and post synaptic membrane seperated by 20nm synaptic clefts

axodendritic synapses axosomatic synapses axoaxonic synapses >1 NT can be found in 1 synapse

all synapses of individual neuron contain the same mix of NT's

5 major steps

1) synthesis 2) Storage - synaptic vesicalss 3) release -triggered by influx of Ca++ (voltage gated Ca channel) 4)Reception of NT w/ receptors (.3 ms diffusion delay) -effect is dependant on receptor type

5) Inactivation

a) simple diffustion

b) catabolism with synaptic cleft c) reuptake

above is classical synapse two additional types

1) autoreceptors


/ |

pre = <---autotransmitter ...stimulates release from syaptic vessicles but also activates the prenaptic source


2) retrograde neurotransmission

     __    ___

/ | | \_____

pre y | |x ______ <---retrograde from post to pre (example is nitric oxide)

\___| |---/

small -amino acid -amine -acetlycholine -purines (atp/gtp)

large/peptide -at least 50 neuro peptides

aa Nt's -glutamate over 50% of CNS synapes always excitatory many different glutamate receptors clinical importance: -epilepsy = abnormally strong activity of glutamate synapes

overactivation of the nervous system


death of neurons

especially happens in eschemia

GABA (y-aminobutyric acid) major inhibitory transmittor in the brain. opens CL or K channels Clinical importance: plays a role in epilepsy -> decrease in Gaba results in a decrease in inhibition -> overexcited area of the brain

-insomnia -anxiety

glycine present in the brain but is most important in the spinal cord where it is the major inhibitory NT. opens Cl channels

Clinical importance several toxins (such as strychraine) hyperekplexia (startle disease) genetic mutatioin defective glycine receptor

Neuropeptides - neural modulators

> 50 neuropeptides known some widely distributed while som are only found in specific regions normally released only following high levals of activity - bursts or trains of AP in synapeses containing both a aa and a neuropeptide normal -> glutamate high levels -> glutamate + Neuropeptie

clinical importance of neuropeptides

-PAIN = 2 families enkephalins and endorphins

                         bind to opioid receptors

side effects = constipation, slurred speech, drowsiness mental confusion, dependence, addictive behaviors

amine NT's include catecholamines dopamine and norepinephrine and the indolamine sesrotonin present mainly in brainstem nuclei which typically have broad connections throughout the cebreal cortex may be excitatory or inhibitory 5HT1A = Na channel (epsp) 5-HT1B = Cl channel (ipsp)

Clinical importance

dopamine: addiction/schisophrenia and parkingsons disease NE, 5-HT arousal attention mood disorders

acetlycholine - involved in both neural signaling and neuromodulation major transmitter in the PNS also found in CNS over 100 different recptors

clinical importance : alzheimer's disease

can be fast or slow

ionotropic ligand gated ion channels Rapid channels

glutamate , gaba and Ach

slow transmission -> metabotropic receptors (2ndry messanger

modulation of synaptic functions changes in protein expression

Not all synapses use chemical NT very rarely neurons communicate directly via electrical communications

-gap junctions form from connexins electrical synapses found in a few population of neurons which act in unison examples: inspiratory center horizontal cells on the retina

The neuromuscular Junction: synapse bet motor neuron and a skeletal muscle fiber

1 Muscle fiber receives a single synapse NMJ is very large compared to CNS syn

- No summation

  - All NMJs are excitatory
  - end plate potential (muscle fiber response to activation of motor neuron)
 -EPP are always suprathreshold

At NMJ -> Ach is the only NT -> binds to a subset of Ach receptors (nicotinic) nAchR


d-tubocurairine muscle relaxant

botulinum toxin blocks release of Ach from presynaptic terminals interferes with proteins for vesicular fusion

induces descending paralysis clinical boxtox cervical dystonia blepharospasms

Myastenia gravis

autoimmune disease antibodies target the nAchR

increase in nAChR turnover block Ach binding

Clinical manifestation

cardinal features : weakness and fatigue of muscles

myasthenic fatigue cranial muscles -ptosis -diplopia -disarthrea (slurred speech)

Lambert Eaton

myastenic syndrome antibodies against voltage gated Ca channels in NMJ Clincial manifestation muscle weakness affects limb muscles

lambert activity -> strengthens with activity hyporeflexia

most commonly associated with small celled carcinoma of the lung


an automatic response to a stimulus every reflex requires the normal functioning of all its components which in the case of the simplest reflex includes only two neurons one sensory neuron and one motor neuron as well as bein important for normal function reflexes may help the clinician during the diagnosis of disease or injury

reflexes maybe diminished by pathology -sensory nerve -LMN -NMJ -muscle -joint disease

will cause hyporeflexia

reflexes can be increased by disease to UMNs

Anatomy of the reflex are: grey matter in center of spinal cord white matter in the outside sensory afferent neuron --------> cellbody in DRG ------> enters spinal cord and innervates a or motor neuron (in white matter) ---> exits spinal cord -> motor neuron LMN (efferent)

sensory stimuli which activites most reflexes are either

propriorecption where our body is in space -changes in muscle length -changes in joint position -static limb position

nocireception: stimuli that have caused tissue damage or threaten to do so (PAIN) -intense mechanical -noxious cold/heat -exogenous/endogenous chemicals

LMN (efferent limb) neuron which directly innnervates skeletal muscle as a LMN (final common pathway)

LMN cell bodies are found in

anterior ventral horn of spinal cord

axons exist via ventral root also LMN in brainstem in cranial nerve nuclei 9 of 12 CNs have LMNs

axons exit brainstem via cranial nerves

Upper Motor Neuron (UMN) are involved in commanad of LMNs UMN cell bodies are found in numerous locations

-cerebral cortex

-primary motor cortex
-premotor cortex
0supplemantal motor area


-UMN axons travel from Primary cortex to LMNs while matter tracts -> corticospinal tract

normally while at rest UMNs have an inhibitory action on the reflex

Mylenated axons

alpha =LMN ~120 m/s

  Ia muscle spindle afferents
  Ib golgi tendon afferents

AB = vibration, touch ~70 m/s

Agamma = LMN to muscle spindle (gamma motor neuron) As = pain 30m/s B preganglionic autonomics 15m/s

C Unmyleinated axons 2.5 m/s

Reflexes: Deep tendon reflex (stretch reflex, myotactic reflex)

monosynaptic reflex tapping tendon streches muscle which is sensed by the muscle spindles what is a muscle spindle? (proprioception) an encapsulated sensory organ

- intrafusal muscle fibers 
- Ia spindle afferents
- ending of a gamma motor neuron(efferent)

stretch muscle -> activation of by Ia afferents -> axon goes to spinal cord and directly synapses and activates a alpha motor neuron -> activate the extrafusal muscles

activation of agonist muscle + inhibition of antagonist muscle

reflexs tested in a relaxed ina symmetric position test between differences in sides (left and right)

biceps tendon C5,C6 tricep tendon C7 patellar tendon L4 achilles tendon S1

what is the purpose of the gamma motor neuron -> maintians sensitivity of the muscle spindle

what does the golgi tendon do? Ib afferent -> muscle tension force

-> inhibition of agonist muscle -activation antagonist muscle problems seen in clasped knife reflex in paralyzed patients

plantar reflex stroking of lateral margin of plantar surface of the foot reflex = plantar flexion

normal response require UMN input

dorsiflexion in response is called lebanski reflex indicating UMN damage

crossed extensor reflex

corneal reflex - touching cornea induces a blink

nocioreceptors have both afferent and efferent functions

axon reflex

activation of nociereceptor if > threshold results in generation of an AP and release of NT in the spinal cord in an unusual exception to the rule many cutaneous nocireceptors contrain voltage gated sodium channels in their dendrites

LMN lesion give a triad of symptoms -flacid paralysis -hyporeflexia/areflexia -muscle atrophy

UMN lesions symptoms -spastic paralysis (cannot move but resistance is present) -hyperreflexia -Babinski sign


somatic and autonomic motor systems


function of the ANS is to maintain the internal environment of the body maintain homeostasis controls SM, Cardiac M and glands

2 divisions symp para

3rd division enteric

motor system / efferent system

sensory neurons innervate visceral organs and are involved in autonomic funcction/reflexes

activity of the ANS is regulated by the brainstem/hypothalamus and forebrain

Charateristic Somatic Autonomic effectors skeletal m cardiac/ smooth , glands fx adjustments in external stim internal stim

  1. of neurons 1 2

nt's Ach Ach, NE, E receptors N1 (NM) N2(NN) alpha 1,2

                                                           B 1,2 and Muscorinic

target responses EPSP -> threhold Epsps/Ipsps lesions paralysis (paresis) effotrs are still functional but poor control/responsiveness

ANS Synapses at peripheral targets are very different than neuromuscular junction

ANS Postganglionic terminate as a series of swellings called varicositites or junctions

Sympathtetic Division

-flight or fight system:: which means that under extreme situations heightened sympathetic activity prepares the body to make maximum use of its resources

preganglionic neurons are located bet T1 and L2 of the spinal cord

fight or flight system pupils dilate eyelids retract peripheral artery constriction hairs stand erect bronchi dilate hr increases glucose mobilized decrease in digestive activites activation and release of adrenal gland release of epinephrine

Preganglionic neurons are located bet T1 and L2 of the spinal cord

-cell bodies are in the intermediolateral cell collumn of the spinal cord T1 - L2 Preganglionic axons are short and myelinated exit spinal cord via ventral root may ascend or descend several levels within sympathetic chain

either synapse in paravertebral sympathetic chain ganglia release Ach bind to N2 AchR or form splanchinic nerve and synapse in preveterbral ganglia -ganglia in cardiac plexus celiac ganglia superior mescenteric ganglion inferior mesenteric ganglion


axons are long and unmyelinated release NER exception is sweat glands which releaese Ach

Parasympathetic rest and digest pupil constriction salivation lacrimation decrease in hr increase in GI activity swelling of gential erectile tissue

preganglionic neurons found in brainstem and sacral spinal cord -long and mylineated

synapse within ganglia located near target organ releaese ACh binds to N2 AChR

preganglionic parasympathetic neurons in the brainstem

-edinger westphal nuclues midbrain CNIII -pupil constriction -lens accomadation

-superior salivatory nucleus (pons) CVII (facial nerve) lacrimal glands salivation except parotid

inferior salivatory nuclues medulla CN9 parotid gland -glossopharyngeal nerve

dorsal motor nucleus of CN 10 and nuclueus ambiguous Vagus parasympathetic of the heart lungs most of the GI tract to the splanic flexure

preganglionic parasympathetic neurons in the spinal cord lateral horn of S2-S4

lower colon and rectum detrusor cavernous tissue of penis/clitoris

postganglionic short and unmyleinated release AcH binds muscarinic AChr

General rule most organs have dual innervations and the 2 divisions have antagonistic influences on target organ function

modification: salivary glands dually innervated ->

sympa stimulates viscous saliva para symph stimulates watery saliva


-most areterioles -adrenal medulla -piloerector muscles -sweat glands

enteric nervous system consists of 2 layers of neurons in SM of the gut the myenteric and submucosal plexus

able to funcioin independantly of SNS/PNS control activity of plexuses modulated by dual symp/parasump innervation innervation ENS = postganglionic

central control of visceral motor functions begins with afferent information about the status of visceral organs visceral afferent cellbodies in dorsal root ganglia or sensory ganglia of cranial nerves 9 and 10 (glossopharyngeal nerve, vagus nerve)

viseral sensory neurons activated by:

physiological stimuli -normal levels of stretch -chemistry

  -co, o2, pH

-> axons travel w/ parasymp fibers (primarily via vagus)

nociceptive stimuli -stretch -ischemia -chemistry (lactic acid) -> axons travel via symp enter at T1-L2 autonomic dysreflexia

-visceral afferent informatin relayed to the medulla specifically to the soltary nucleus (nucleus trractus solitarius)

involved in autonomic reflexes relay center to other regions of the brainstem relay to hypothalamus

higher order structures in autonomic nervous system inclujde hypothalamis amygdala, prefrontal cortex entorhinal cortex and other forebrain nuclei


  -> paraventricular nuclei -> hypothalamospinal tract

NT, receptors and the ANS

ganglionic NTs -release Ach -> bind to N2 AChR

junctional Neurotransmission (postganglionic to target signaling )

symp -> NE except for sweat glands Ach -> mAChR)

para -> Ach

Symp adrenergic

2 types

all are 7 TMD g protein coupled receptors alpha and beta are tissue specific all activated by NE and E though varying affinities

postjunctional a1 adrenoreceptors cause contraction of SM in

perippheral arteries dilator pupullae spinchters of GI Tract / bladder vas deferens

prejuctional a2 on parasymp and symp junctions -inhibitory -> decrease in transmitter release


increase in HR increase in Force of Contraction

can be either pre/post

bind to E prejunctionally and promote NE release

postjunctionally inhibit SM contraction


glycogen breakdown in the liver


-all muscharinic AChR , G protein mediated pathway at least 5 subtypes M1-M5 slow and prolonged heterogenous distribution located postjunctionally and prejunctionally

HORNER'S SYNDROME -injury to symp supply to the head/neck


CONSTRICTED PUPIL (myosis) ptosis anhydrosis

or pathological stimuli

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