Prosencephalon

(forebrain)

• Embryonic
• develops into the telencephalon (cerebrum), and diencephalon (subcortical nuclei).
• high-order information processing and executive function

• embryonic
• gives rise to midbrain nuclei

Rhombencephalon

(hindbrain)

• Gives rise to the metencephalon and myelencephalon
• metencephalon develops into the pons and cerebellum
• myelencephalon (aka medulla oblongata)
• part of the brain stem

• diencephalon, midbrain, pons and myelencephalon

• enlargements
• Cervical intumescence: C6-T2 - brachial plexus
• Lumbosacral intumescence: L4-S3 (S5 in large animals) - lumbosacral plexus

• Dorsal horn - sensory function (develops from alar plate)
• Ventral horns - motor function (basal plate)
• Lateral horns (only T1-L3) - autonomic neurons located in the CNS (basal plate)

• functionally related clusters of nerve cell bodies = nuclei
• cerebral cortex and cerebrum - neruron cell bodies form layers (lamina) - also deep seated basal nuclei (cerebrum).

White Matter of

Spinal Cord

• FUNICULUS
• dorsal funiculus - b/w dorsal horns - sensory only (ascending tracts)
• lateral funiculus - b/w dorsal and lateral horns - motor and sensory function
• descending tracts are motor tracts.
• ventral funiculus - b/w ventral horns - sensory and motor.

White matter in

brain stem, cerebellum,

and cerebrum

• diffuse in brain stem - may for fasciculi, tracts, lemnisci, and stria.
• peduncles - b/w cerebrum and pons
• internal capsule - b/w cerebrum and brain stem

• joins 2 segments of cord at dorsolateral sulcus
• dorsal root contains afferent sensory fibers entering the spinal cord.
• may then synapse w/in spinal cord or ascend to the brain
• dorsal root ganglion - in PNS - nerve cell bodies of sensory fibers.

• Joins 2 segments of SC at ventrolateral sulcus
• contains efferent motor fibers
• neuronal cell bodies are within the ventral horn or lateral horn of some segments.
• no associated ganglia
• nerves divide into spinal dorsal and ventral branch
• T1-L3 - ramus communicans - lead to autonomic ganglia.

• under skull
• dura mater - most external
• arachnoid and pia - leptomeninges
• subarachnoid space continuous with ventricles filled with CSF
• outside of the CNS

Glial Cells

PNS

• satellite cells - surround nerve bodies
• neurolemmocytes (schwann cells) - myelinate axons
• myelin - high lipid content
• one schwann cell to one fiber
• if it doesn't myelinate - cradles in several processes.

• oligodendrocytes - myelinating cells of CNS - one oligo to many fibers.
• astrocytes - cover surface of CNS capillaries --> BBB
• microglia - macrophages
• ependymal - line ventricles/central canal - filter CSF

• unipolar - one process (functionally an axon and a dendrite) - splits into 2 away from cell body - dendritic zone and an axon. EX - sensory neurons
• bipolar - one dendrite, one axon - retina, inner ear, olfactory epithelium
• multipolar - several dendrites - one axon - most common - striated muscle

• organization based on functionality and elecrophysiological networks.
• involves intensity and timing of neuronal firing
• uses sensory networks, motor networks, higher order networks
• high-order networks poorly understood
• high order: emotions, memory, endocrine

• chemical receptors
• mechanical receptors
• specialized receptors (retina, temp)

• lower motor neurons - connect CNS to muscle
• upper motor neurons - connect brain to lower motor neurons.
• Most neurons are associative - involved in interconnections w/in brain

• nerve to muscle
• skeletal muscle - motor neuron axon branches to contact multiple fibers
• sarcolemma folded with receptors
• motor unit: neuron and associated muscle fibers.
• smooth muscle: axons have a series of swellings along length - varicosities - fuse with axolemma
• no modification of sarcolemma of smooth muscle

• pore size - determines which ions can pass: large ions (K+, Cl-), small ions (Na+, Ca2+)
• ion filters - within the pore of the channel (intrapore) - highly selective for binding of ions - may be specific targets of drugs - anesthetics and K+ channels
• channel gates - inactivation gate - if nongated, flow determined by concentration gradient, size, ion filter.

• fluctuations b/w open and close depends on:
• kinetics of voltage dependent channels - how fast/slow the gate opens/closes
• conc grad
• current running through a channel determines how quickly ions can pass - influenced by Vm
• conc of ligand for gated channel

• neuron equilibrium - determined by conc grad and relative permeability of membrane to ions
• -70mV
• at rest - K+ and Cl- channels are open, Na+, Ca++ are closed.
• Na+ - more conc outside
• K+ - more conc inside

• RT/zF = 61
• E=61log (conc. out/ conc. in)
• K+ = -96mV
• Na+ = +59 mV
• changes in conc grad inside and outside cell alter the equilibrium potential
• larger gradient - larger equilib potential

• to maintain conc gradients - keep Na+ out of cell - keep channels closed at rest
• membrane is slightly leaky to Na+
• 3 Na+ out, 2 Na+ in

• subthreshold (-40mV) stimuli - depolarizing or hyperpolarizing.
• summation: spatial (2+ applied at diff locations at same time), temporal (2 of same stimulus at diff times)
• local currents, short lived (temporally and in distance)

• EC Ca2+ conc
• can potentially block Na+ and K+ channels - changes in membrane potential more difficult
• increases in Ca2+ EC will increase threshold
• decreases in Ca2+ will decrease threshold

• giant squid axon
• showed the propagation and recovery of an action potential

1. summated GPs reach -40mV threshold - large # of voltage Na+ channels open - Na+ enters cell - depolarization
2. influx of Na+ -> +59mV - voltage-gated K+ channels activated slowly, flow of Na+ slows b/w reach equilib potential, K+ flows out - efflux of +ve charge- repolarization
3. secondary gating of Na+ channels - block Na+ influx - refractory period.

• stimulus -> local current flow -> depolarization of adjacent membrane
• Na+ out and K+ in occurs along entire length of the axon
• AP prop via ionic conductance
• unidirectional b/w of refractory period

• largest and fastes
• b/w schwann cells - interfiber nodes of Ranvier
• myelin insulated preventing ion leakage or diffusion except at nodes - high conc of Na+- conduction of AP at this point.
• Saltatory conduction

• MS - genetic - myelin degradation - progressive nerve paralysis
• canine shaking pups - genetic myelin disease in dogs - reduced size at birth - usually survive for 2 years.
• visna/ canine distemper - inflammatory myelin diseases - sheep and dogs - ataxia, paresis, depression.

• stabilizes membranes - keeps Na+ channels closed
• when Ca2+ deficient - nerves have increased permeability to Na+, spontaneously excitable
• muscle spasms and rigidity

• hypoxia, toxins
• local anesthetics - 'caines' - block voltage-gated Na+ channels - no pain transmission to brain
• preferential action on small unmyelinated nerves (pain nerve fibers)
• Tetrodotoxin - TTX - fish and some bacteria - block voltage Na+ channels -> paralysis
• Saxitoxin (STX) - marine dinoflagellates, cyanobacterium - blocks many Na+ channels - paralysis, loss of excitability.

• large - peptides - synthesized in cell body, vesicles transported down axons to terminasl
• small - glutamate, GABA, ACh, NE - synthesized and packaged at nerve terminal - enzymatic production

1. vesicle associate proteins synthesized
2. transport to packaging sites in axon terminal - motor protein, cytoskeleton
3. maturation of vesicles - active packaging of NTs
4. reserve pool of vesicles
5. APs depolarize terminal - Ca2+ enters via voltage gated channel
6. vesicles mobilized - active zone on pre-syn membr.
7. vesicles docked and exocytosed
8. NT release - recycled into buton or enzymatically degraded

• require ATP for activity of ca/calmodulin kinase II (CaMKII) and myosin light chain kinase (MLCK)
• both phosphorylate proteins that are substrates for mobilization of synapsin I and myosin II - prime vesicle for movement to active pool

• calcium sensing protiens -
• synaptotagmin - only binds SNARE complex of proteins once bound by Ca2+
• SNARE components
• VAMP-2 (synaptobrevin) syntaxin I, SNAP-25 - important for vesicle fusion.

• time b/w pre-synaptic release of NT and post-syn response
• time take for NT discharge, NT diffusion across synapse
• binding of NT post
• response of post-syn membrane

• ACh release onto NMJ - binds ACh-gated Na+/K+ channels - open - Na+ influx - depolarization
• generates an end-plate potential (graded potential)
• AP generated in both directions along sarcolemma
• ACh metabolised by AChE
• all input to NMJ is excitatory
  

• ACh antagonist
• binds ACh receptors - no activity - competitive inhibition of ACh
• not susceptible to AChE
• flaccid paralysis, death by asphyxiation

• AChE inhibitor
• neostigmine, physostigmine
• ACh not metabolized
• muscles repeatedly stimulated - spasms
• laryngeal spasms - suffocation - death.

• ACh agonist - muscle spasms
• not susceptible to AChE but still active

• clostridium botulinum
• prevents release of ACh from nerve
• targets SNAP-25
• prevents docking and secretion of ACh

• decreased numbers of ACh receptors at NMJ
• autoimmune disease
• muscle paralysis
• ACh still released
• AChE blockers - (neostigmine) - transient relief of symptoms.

• pariparturient muscle weakness
• low blood calcium at onset of lactation
• failure to transmit nerve signals across NMJ

• catecholamines (Da, NE)
• serotonin
• histamine

• glycine
• glutamate
• aspartate
• GABA

• Substance P
• enkephalins, endorphin, bradykinin, bombesin, somatostatin, VIP, cholecystokinin-like peptide, neurotensin, insulin, gastrin, glucagons, TRH, GnRH, ACTH, angiotensin II, ADH, ocytocin, Prolactin, etc.

• glutamate - excitation usually - neurons are long-distance projection neurons - across different modules of brain.
• GABA - inhibitory - mostly local networks, inhibition of "circuits"

• Ionotropic - ligand-gated ion channels - more rapid transmission
• metabotropic - intracellular signalling - ex - GPCR - takes longer b/w of cell signalling.
• receptors can be recycled

Glutamate Receptors

Ionotropic

• NMDA - most common - can pass Na+, Ca2+, K+ depending on state - mostly Ca2+
• AMPA- same - except gated mostly for Na+ and K+
• Kainate receptor - selectively activated by kainite - conduct Na+ and K+ ions

Glutamate Receptor

Metabotropic

• GPCR
• 3 classes
• 1) mGlu1 mGlu5 - trigger Phospholipase C and Ca2+ signalling
• 2 and 3) mGlu 2-4; 6-8 - coupled to adenylyl cyclase - makes cAMP - negatively coupled
• expressed by glial cells (astrocytes) - regulate availability of glutamate to environment
• control excitotoxicity to glutamate signalling

GABA receptors

Ionotropic

• GABA-A
• related to alpha-adrenergic and glycine receptors
• ligand gated Cl- channels - Cl- enters cell, hyperpolarized.
• inhibits generation of APs

GABA receptors

metabotropic

• GABA-B
• GPCR
• influence K+ and Ca2+ conductance in post membr.

• lateral inhibition - focuses transmission of neural signals
• neighbouring GABA neurons "damped" glutamate released

• long-lasting increase in responsiveness of post neuron to specific pre input given in trains
• neuronal learning - in hippocampus
• dependent on NMDA and AMPA glutamate receptors
• blocking NMDA - prevent LTP - activated by glu. - increase IC Ca2+ activates CaMKII - activation of AMPA, increase in AMPA receptor on post
• increased gene expression required
• retrograde messages from post neuron to pre important

• inhibit synthesis (DON and MSO - inhibit glutamate synth)
• block reuptake (resperine - 5HT, Da, NE reuptake)
• mimic NT (nicotine - ACh, LSD - 5HT, tranquilizers - GABA)
• inhibit release of NT (botulism)
• block degradation of NTs in cleft (amphetamines block DA and NE degradation)
• Synaptic fatigue - exhaustion of NT stores - need to make more - ex seizure

• tactile information - touch, pressure, vibration
• proprioception - limb, muscle, joint
• pain
• temp

• free nerve endings - mechanical, thermal, noxious
• Merkel's discs - expanded tip - sustained response to vibrations 5-15Hz
• Meissner's corpuscles - dermis of glabrous (hairless) skin - low frequency - 20-40 Hz
• Pacinian Corpuscles - deep layer of dermis - 150-300 Hz
• Hair follicle endings - hair displacement
• Krause's corpuscles - dermal layer of lips, tongue genitals - pressure detection
• Ruffini's end-organ - dermis of hairy and glabrous skin - pressure

• axon with unmyelinated tip - encapsulated by concentric layers of CT capsule - each layer separated by viscous fluid.
• conversion of mechanical to electrical
• pressure -> deformation of capsule - fluid compressed, axon tip deformed - mechanically-gated Na+ channels open - graded potential -> AP generated at 1st interfibral node -> CNS via dorsal root
• respond to intensity, receptor potential magnitude, AP frequency
• greater pressure, larger graded potentials, more AP generated in neuron.

Pacinian Corpuscle

Adaptation

• most somatosensory receptors - attenuated response to constant stimulus.
• 1) physical property - fluid eventually redistributes with constant pressure - equalizes pressure on both sides of axon - axon regains shape - diminished capacity for stimulus to generate graded potential
• 2)nerve fiber accommodation - slow recovery of ion gradients after multiple stimuli. Decrease in number of ions available

• Pacinian
• hair receptors
• semi-circular canal receptors
• adaptation allows for detection of changes in rate of stimulus

• detecting general status of incoming stimuli
• muscle spindles
• golgi tendon organ
• pain receptors
• baroreceptors/chemoreceptors
• provide constant information about stimuli status to CNS

Relay of somatosensory

to CNS

CIRCUIT!

• DORSAL SPINAL BRANCHES
• cell bodies - in dorsal root ganglia
• axons travel via dorsal funiculus (dorsal lemniscal track)- no synapsing
• synapse in nuclei of myelencephalon (gracile and medial cuneate nuclei)
• Second order neurons project across to contralateral side of myelencephalon - enter medial lemniscus to ventrobasal thalamus (diencephalon)
• tertiary neurons - in thalamus - send sensory info to somatosensory cortex - somesthetic interpretation of info (unknown mechanism)

• vestibular input
• muscle spindles (stretch)
• golgi tendon organ
• Ruffini's endings
• Pacinian corpuscles (joints)

• extrafusal fibers - contraction
• intrafusal - in the middle - wrapped by nerves
• spindle is paralell to extrafusal
• muscle stretch - mechanically gated Na+ channels on nerve endings open -> graded potential -> AP-> CNS
• CNS response via gamma motor neurons - axons innervate small contractile muscles at 2 ends of each muscle spindle
• alpha motor neurons signal motor contraction in extrafusal

• primary sensory neurons - dendrites intertwined with collagen fibers in tendons
• depolarized when muscles contract (opp of spindle)
• contraction - increased tension in tendon - stimulation of mechanically gated ion channels on dendrites of neurons

Unconscious proprioception

transmission to CNS

• DO NOT CROSS MIDLINE
• if from pelvic limb - synapse in nucleus thoracicus
• if from thoracic limb - enter dorsal funiculus w/o synapse - travel ipsilaterally and synapse in lateral cuneate nucleus in myelencephalon
• dorsal spinocerebellar track/cuneocerebellar track - axons terminate in cerebellum

• A-delta - extreme pressure/heat - myelinated, fast fibers
• C-delta - slowest conductivity of all fibers - unmyelinated - stimulated by noxious stimuli - pressure, temp, chemicals
• Peptidergic fibers - secrete substance P in spinal cord
• Nonpeptidergic - glutamate and other transmitters

Transmissin of Pain Info

to CNS

• spinothalamic track
• axons from pain neurons synapse in dorsal horn
• some fibers cross contralaterally, others stay ipsi
• opiate influence - interneurons and projections from periaqueductal gray of brain stem
• multisynaptic
• ultimately synapses on ventrocaudolateral nucleus of thalamus - may also involve perception of pain

• caudal to post-cruciate gyrus in parietal lobe
• primates - face, hands, and figers have a high number of sensory receptors - larger representation in homunculus.
• mice - whiskers and nose important - altered representation.
• right side of body on left side of brain and vice versa
• b/c of crossing of sensory fibers prior to thalamix synapse.

• close object - ciliary muscles contract, zonular fibers relax - lense bulges into sphere
• far object - ciliary muscles relac, zonular contract - flattens the lens.
• accomodation

1. photoreceptor layer - contains rods and cones - very back of retina
2. bipolar cells - also interneurons and amacrine cells
3. ganglion cells - at surface, in contact with vitreous humour.

• Centre of the retina - fovea
• cones mostly central, more rods peripherally

photoreceptor activity

in dark

• outer segment as opsins and ligand gated (in response to intracellular molecules) Na+ and Ca2+ channels
• binding of cGMP opens channels - activation
• in dark, IC conc of cGMP high, cells are "active" - tonic depolarization - release of glutamate.

Photoreceptor Activity

in light

1. photos of light isomerize vitamin-A portion of opsin
2. free opsin activates G-protein tansducin
3. GPT activates phosphdiesterase
4. PDE hydrolyzes cGMP molecules - decrease in cGMP - closing of Na+, Ca2+ channels - decreased activity of photoreceptors - less glutamate released from the cell.

1. light decreases glutamate release by photoreceptors (glutamate is inhibitory on bipolar cells)
2. inhibition removed and bipolar cells activated
3. bipolar cells activate ganglionic cells
4. ganglionic cells send axons through optic nerve to lateral geniculate nucleus (metathalamus)
5. LGN relays infor to primary visual cortex - occipital lobe
6. REMEMBER - ganglion cells on medial cross at optic chiasm - on lateral - stay ipsilateral (left goes through right LGN, right goes through left LGN)

• Rods - high convergence, high sensitivity to light, night vision, low acuity, black and white
• Cones - low convergence, low sensitivity to light, day vision, high acuity, 'see' colour

• light adaptation - prolonged exposure to light - breakdown of rhodopsin faster than it reforms, less sensitive to light
• dark adaptation - vitamin A mobilized for synthesis of rhodopsin - not being broken down in absence of light - rhodopsin levels increase - increased sensitivity to light.

• optic tract projects here too
• detection of day and night
• involvement with circadian rhythm

• axons also go to brain stem nuclei involved in eye movement and those involved with turning the head.

• 2 streams in cortical information
• dorsal stream - movement and spatial information - where
• vental stream - object info - what

• 2 flexible membranes - vestibular and choclear window
• 2 chambers filled with perilymph - scala vestibuli and scala tympani - separated by basilar membrane
• hole in basilar membrane - helicotrema - allows flow of perilymph
• hair cells embedded in basilar membrane

• Organ of Corti
• tectorial membrane that lies on top of organ - contacts stereocilia projections of hair cells
• tectorial membrane relatviely inflexible - movement relative to the tectorial membrane causes deflection of cilia

• vibration in perilymph - vibration of basilar membrane
• cilia deflected as tect. mem. doesn't move
• Na+ channels open in hair cell - mech gated - depolarization
• deflection toward thickest cilium - depolarization
• opposite direction - hyperpolarization
• seen as waves of depolarization/hyperpolarization

• hair cell depolarized
• release of glutamate and activate ligand-gated glutamate receptors on afferent auditory gibers
• auditory nerve - bodies in spiral ganglion of CN 8

• Pitch detection
• higher frequency detecting cells - basal end
• low-frequency - at apical end of choclea

• also - louder sound, larger vibration, higher frequency of AP -> loudness of sound

• from inner ear -> medial geniculate nucleus of metathalamus
• MGN -> auditory complex

Semicircular Ducts

Anatomy

• 3- contain vest. sensory receptors - detect rotational motion of head and body.
• 3 canals - rostral - angular motion in saggital plane, horizontal - horizontal angular motion, caudal - angular motion in transverse plane

Utricle and Saccule

Anat

• detection of linera movement
• motion due to gravity (vertical acceleration)
• horizontal acceleration
• maculae - sensory organs - contains hair cells that protrude into gelatinous mass
• otoliths - CaCO3 crystals - in gel - movement of otoliths in response to movement activates vest. hair cells.

1. deflection of vest. hair cells b/c of movment of otoliths - depolarization OR hyperpolarization
2. movement towards larest cilium (depolarization), movement away (hyperpolarization)
3. activation - release of glutamate
4. hair cells of SSDs - single tuft at base of SSD (cupula of Ampulla) - same mechanism

• keep eye focused while head moves
• vestibular nerve synapses in vestibular nucleus - project to contralateral abducens nucleus (CN 6) - then to the right lateral rectus muscle of the eye
• also to the ipsilateral oculomotor nucleus (CN 3) - stimulates ipsilateral medial rectus muscle
• ultimately, eye will rotate opposite to direction of head movement in horizontal plane.

Motor Function

Brain Stem Nuclei

1. control of postural support of muscles - extrapyramidal pathways (ventra tracts of brain stem) - reticulo-spinal, vestibulo-spinal, rubro-spinal (red nucleus from cerebellum), tecto-spinal tract (visual) 
2. control of unconsious, stereotyped movement - modulation of tone in extensor muscles - control of gait - red nucleus - influences CPGs - in non-primate animals - most importnat centre for control of gait (more control over forelimbs/shoulders? - analagous to humans?)

• damage to - ataxia
• function in coordination of motor function
• execution of rapid movements
• receives a copy of output from motor cortex (red nucleus), provides error correction, then back to nuclei/cortex.

• basal nuclei - striatum (caudate/putamen), globus pallidus (GPe, GPi) - input from all cortical areas and substantia nigra (DA production)
• process and send info to same areas via thalamus (Subthalamic nuclei) - sent to cortex as motor plan
• basal nuclei may be important in initiation of movement once plan in reached
• maintenance of inhibitory function
• more important in animals for conscious control of movement.

Cerebral Cortex

Motor Cortex

• over-representation of areas of body associated with finely controlled movement.
• right side of body in left cortex
• corticospinal pathway/ pyramidal tract - conscious motor output - from motor cortex - fibers pass directly into spinal cord after crossing at level of myelencephalon
• for learned, skilled, fine, voluntary movement of flexors

• ACh release as neuromodulator in brain
• in nucleus basalis - diencephalon - wide-spread ACh input to cortex
• ACh releasing neurons also to pedunculopontine area of the pons - project to the thalamus
• receptors: nicotinic - ligand-gated Na+/K+ channels (fast) muscarinic - GPCR(slower response)

• in locus coeruleus of brain stem
• important in limbic system - emotion, endocrine function
• receptors: alpha and beta - all are GPCR

• in raphe nuclei - project to entire cortex and subcortical nuclei
• receptors: at least 13 different ones - most are GPCR
• 5HT3 - ligand gated Na+/K+ channel

• substantia nigra (midbrain)
• strong projections to frontal cortex
• pathways:
• 1) mesocortical - DA to frontal cortex,
• 2) mesolimbic - DA to limbic (ventral) striatum of basal nuclei

• 5 subtypes
• most GPCR -
• D1 and D5 - increase Vm
• D2,3,4 - decrease Vm
• D1,D2 - in striatum - unconsious motor control
• D1,D5 - cortex - cognitive and executive CNS fxn
• D3,D5 - hypothalamus: endocrine and autonomic fxn

• binding kinetics of receptor: influences which receptor activated and at what strength (diff receptors for one NM have different affinities)
• influence of receptor activation on post-synaptic cell : hyperpolarization or depolarization?

• NE - arousal/reward
• DA - motor/reward/cognition/CNS endocrine, nausea
• 5HT - sleep/mood/satiety/body temp
• ACh - arousal/short term memory(attention)/learning
• effects modulated by location and amount of specific receptors throughout the CNS

• abnormal 5HT pathway
• may be a genetic mutation in 5HT transporter gene
• malfunction of communication b/w frontal cortex and basal nuclei
• orbital and medial frontal cortical areas (OMFC) - send signal to thalamus to get more info about stimulus
• then back to OMFC -> motor response to caudate nucleus - malfunction leads to constant stimulation of caudate nucelus -> motor responce

• glutamate - ionotrophic - Na+, K+, Ca2+
• ligand and voltage gated
• Mg2+ block channel - voltage dependent
• Zn2+ block non competitively and voltage indep - both need to be removed
• antagonists - detromethorphan, dextorphan, ehtanol, ketamine, NO, methadone

Tapetum Lucidum

Diseases

• some animals naturally lack tapetum - white coats, small dogs.
• tapetal degeneration - nutrition-induced (Zn2+ def)
• chemical-induced (Zn-pyrithione in shampoo
• hereditary - autosomal recessive - beagles