Upper Motor Neurons (UMN)

basic pathways

• from brain to spinal cord
• from primary motor cortex -> internal capsule -> midbrain (cerebral crus) -> pons (descending fibers in bundles interspersed with pontine nuclei and transverse pontine fibers) -> medulla (reform one bundle = pyramids) -> caudal medulla (fibers cross = decussation - cross midline) (90%  cross here) -> lateral corticospinal tract
• at cerebral crus, only 10% end up going to spinal cord, most end up in pons-> cerebellum
• axons from cortex descend through brain, cross midline and form lateral corticospinal tract to activate local circuit neurons or act on LMN directly
• descending pathways from brainstem control postural mucles and these pathways usually run bilaterally
• lateral white matter/lateral corticospinal tract = axons from motor cortex, controls distal muscles
• medial white matter = axons from brainstem, controls axial muscles, bilateral control of medial muscles
• go down pyramidal tract & then decussate and go down lateral corticospinal tract
• CS tract directly synapses on finger muscles

Reticulospinal

Rubrospinal

• brainstem nuclei that affect LMNs
• Reticulospinal - from reticular formation (RF) with inputs from cortex, cerebellum, and vestibular nuclei/ventromedial paths of UMN - medial reticulospinal from pontine RF activates exensors and higher centers inhibit; and lateral reticulopsinal from medullary RF activates flexors and higher centers activate, cortex cerebellum & vestibular inputs to RF
• Rubrospinal - from red nucleus - inputs to red nucleus from corex & cerebellum, and facilitates flexors in contralateral upper limbs

• amyotrophic lateral sclerosis, Lou Gehrig's disease
• scarring in lateral CS tract
• get weakness, fasciculation & then spasticity as UMN affected
• loss of muscle tone, atrophy of muscles
• if get in frontal lobe -> frontotemporal dementia
• degeneration of LMN (and some UMN)
• ~ 0.05% in USA, fatal within 3-5 years, usually by respiratory failure
• ~10% familial, and 25% of these are mutation in superoxide dismutase (SOD1)
• many links to genetic mutations:
• SOD1-aggregates form in cells - can be transferred to other neurons too
• RNA binding proteins e.g. TDP43 stress and TDP43 accumulates in granules
• repeat expansions eg C9orf72
• ubiquitination and proteasomal proteins affected
• excitotoxicity
• cellular transport
• SOD1 knockout mice have symptoms of motor neuron disease, but no effects on LMN & UMN - do mutan SOD1 and get LMN/UMN disease (gain of function)
• wild type SOD1 transgenic mice: neuroprotective feautures
• aggregates toxic RNA & toxic peptides, aberrant protein processing in proteasomes, altered axonal transport, altered RNAproceessing, stress granules

SMA

- general info & treatment

- the 3 types

• spinal muscular atrophy
• autosomal recessive disease characterized by rapid degeneration of LMN in anterior horn due to reducedsurvival motor neuron (SMN) protein
• leading genetic cause of infant mortality in US & Western Europe (1/6000 live births) and carrier frequency of 1/40
• SMN is protein involve din assembly of snRNPs t/f splicing defects especially in spinal motor neurons. Also functions in transcriptional regulation, telomerase regeneration & cellular trafficking & possible neuronal migration and/or differentiation
• worse when there are bigger deletion sin SMN gene
• when SMN1 gene gone/non-functional, promote activity of SMN2 gene (increase transcription).
• Try to inhibit histone deacetylation so transcription of SMN2 increased
• NSAID , indoprofen also promotes SMN2 expression
• Aclacinomycin & topoisomerase II inhibitor but toxic
• mice without SMN genes lethal, but if express SMN2 get SMA wth less severe  symptoms the more protein is expressed
• SMA type 1: obvious by 6 months, hypotonia, diminished limb movements, lack of tendon reflexes, fasciculations, tremor, swallowing & feeding difficulties, impaired breathing - most children never sit or stand & die of respiratior failur before 2 years
• SMA type II: begin between 6 & 18 months, may be able ot sit but can't stand or walk un-aided &  may have respiratory difficulties, including increase risk of respirator infelctions, life expectancy into adolescence or young adulthood
• SMA type III: Kugelberg-Welander disease: appear between 2 & 17, abnormal gait, difficulty running, climbing steps, rising from chair, fine tremor of fingers. Lower extremities most  affect. Complications of scoliosis & joint contractures - chronc chortening of muscles or tendons around joints, caused by abnormal muscle tone & weakness, which prevents the joints from moving freely. May be prone to respiratory infections

• multiple sclerosis
• acquired demyelinating
• immune disease that affects neurons
• most common disabling neurological disease of young adults (usually occurs 20 - 40 years old)
• in more polar regions of globe (worse further from equator & if you move to different region of the word before 15 you acquire the new region's risk of MS)
• more in females
• very unpredictable course of disease, but most have short periods of symptoms followed by long stretches of relative relief
• neuroinflammatory disease that affects myelin & nerve cell bodies in brain, spinal cord, and optic
• as disease progresses, get cortical atrophy
• term referes to the distinctive areas of scar tissue (sclerosis or plaques) that are visible in the white matter of people who have it - glia has tried to help and made hard glia scar

• myasthenia gravis
• neuromuscular junction Abs to AChR
• LMN syndrome
• chronic autoimmune neuromuscular disease varying degrees of weakness of the skeletal voluntary muscles
• most individuals have normal life expectacny
• muscle weakness increases during periods of activity & improves after periods of rest
• often affects cranial nerves esp muscles that control eye & eyelid movement, facial expression, chewing, taling, and swallowing
• muscles that control breathing & neck & limb  movements may also be affected
• caused when antbodies block, alter, or destroy receptors for acetylchoine @ neuromuscular junction
• minority of cases are congenital (defect ChAT, AChR, or AChE)
• LEMS reduces Ca2+-stimulated vesicular ACh release (botulinum toxin too)
• AChE inhibitors effective

• muscular dystrophy
• defective protein in muscle

Parkinson's Disease

description & causes

• loss of DA neurons in substantia nigra - 60-80% lost when start to be symptomatic
• normally lose 5-8% of DA neurons/decade
• get reduced activity in direct pathway and increased activity of indirect pathway
• synergistic effects
• nondeclarative memory & emotion also affected
• more difficult to move - hypokinetic
• mostly sporadic (environmental toxins? MPTP)
• tremor at rest
• slowness of movement
• akinesia (no movement) & bradykinesia (slow movement)
• stiffness and rigidit of movement esp extremities
• minimal facial expressions
• stooped over when walking, shuffles feet and doesn't swing arms, getts fastr and faster and balance no good
• overall incurable & debilitating
• causes:
• 10% familial due to mutations in
• A-synuclein (in Lewy bodies), people with sporadic form of PD contained aggregates of a-synuclein
• Parkin-an E3 ligase, loss of function mutation, part of ubiquitin-proteasome system, may lead to accumulation of toxic proteins, normal function probably in synaptic vesicle recycling 
• PARK6 & LARK2 (Dararin) in mitochondria, mutations in this gene may increase susceptibility to cellular stress
• DJ-1 (PARK7) involved in regulating gene activity and in protecting cells from oxidative stress
• risk factors:
• living in industrialized world (environmental toxins?)
• previous head injury
• history of depression
• living in rural area
• drinking well water
• being a farmer, rancher, fisher, or welder
• frequenyt exposure to solvents
• MPTP and sensitivity of dopaminergic neurons to oxidative poison ~ environmental toxin hypothesis 

• degeneration of striatal neurons due to CAG repeats on Huntingtin protein
• encodes a large protein, 3144 amino accides, ~ 348 kilodaltons
• normal populations - 11-34 CAG repeats (codes for gln in protein)
• HD individuals - 42-66 CAG repeat
• diseased form has many extra glutamine residueson protein and protein expressed in many neurons so not sure why only medium spiny neurons affected
• larger number of repeats = usually more rapid progression & earlier onsent
• "anticipation" = earlier onsent in successive generations
• causes increase activity in indirect pathway = more spontaneous movements = hyperkinetic
• ~30,000 people in USA, 1-3% are sporadic with no family history
• early symptoms
• athetosis  (writhin in destal extremities), chorea (abnormal involuntary movement), mood swings, depression, irritability, trouble driving, learning new things, remembering a fact, decision making, change in personality, suspiciousness, rapid jerky motions with no purpose
• late symptoms
• concentration problems, trouble eating & swallowing
• cortical atrophy
• usually fatal within 15-20 years, death due to infection but suicide is also very common
• BDNF CNS knockout mice more closely resembled huntington's than huntingtin mice

• caused by damage to sub thalamus, and this subthalamus has a glutamate input onto medial pallidum
• hyperkinetic
• often do to vascular damage (tumors)
• whole limbs flung in unwanted movements
• temporary

Parkinson's Disease

Treatment

• drugs to increase DA in striatum - most effective at treating bradykinesia and rigidity, less effective w/ tremor and balance. Side effects of unintentional movements (dyskinesias)
• Levidopa + carbidopa (carbidopa delays conversion of levodopa into DA until it reaches the brain)
• D3 agonists
• MAO inhibitors
• anticholinergics - can help control tremor, rigidity
• antidepressants - control depression
• gene therapy - - implanting cells into striatum that make DA (express tyrosine hydroxylase)
• neural grafts with fetal stem cells - needs more work, need to correctly identify cells and promote differentiation
• basal ganglia/thalamus ablation
• pallidotomy - remove part of globus pallidus - alleviate rigidity - liqN2 probe used to freeze and destroy brain tissue
• Thalamotomy - remove part of thalamus
• deep brain stimulation - implant battery-powered generator units bilaterally into internal globus pallidus or sub-thalamus and over-ride abnormal firing patterns

Lower Motor Neurons

(LMN = alpha-MN)

• from spinal cord to muscle
• have cell bodies in ventral horn of spinal cord and project to somatic muscle fibers to control voluntary movement
• cell bodies organized somatotopically
• medial = proximal (like hip); lateral = distal (like foot)
• reflexes important
• fast axons, large diameter, very myelinated
• synapses with multiple muscle fibers
• don't get synapses from cerebellum & basal ganglia because they are modulatory
• Loss of LMN -> weakness, decreased reflexes, decreased tone, paralysis, severe atrophy of muscles

• 1 alpha-MN and the multiple muscle fibers it synapses with
• muscle fibers have ACh, ionotropic cells
• a-MN is highly myelinated & fat to travel fast
• synapse on motor cells in periphery
• 1 motor cell to 1 motor neuron
• 1 motor neuron can go to many muscle cells

• extrafusal muscle fibers = main muscle
• intrafusal muscle fibers = stretch, gamma (propriospinal/annulospiral) = smaller diameter, less myelinated
• gamma neurons make sure intrafusal does the same thing as the muscle around it (extrafusal)
• afferent signals muscle stretch & synapses in spinal cord & activates LMN to cause muscle contraction and gamma-motor neuron to contract muscle spindle fiber
• intrafusal needs to contract to stay senstive to muscle stretch & adds to muscle tone

• inverse myotactic reflex
• signal muscle tenson so get muscle relaxation
• GTO detect muscle contraction on the tendons, innervate neurons to relax
• GTO has excitatory synapse (dorsal root) on interneuron (in gray matter of spinal cord) that has inhibitory synapse on lower LMN (ventral root) 
• prevents tendon tear
• GTO = Ib afferent fibers

• when a flexor contracts, have to relax the antagonist extensor muscle
• reflexes allow for muscle tone and spinal cord circuitry can signal complex movements due to reflex
• reflexes are important and play a role in complex pattern generation (in spinal cord)
• can even cut at spinal cord & cut sensory input
• propriospinal, don't know what legs are doing

• lateral propriospinal neurons innervate LMN to distal muscles and only extend over a few spinal cord segments (cervical & lumbar enlargements)
• medial local circuit neurons innervate LMN to axial muscles & extend over several spinal cord segments
• propriospinal also have anticipatory maintenance of body posture

• corticobulbar neurons from cortex to brainstem - innervate cranial nerve nuclei, reticular formation, red nucleus & basal pontine nuclei (to cerebellum) (often called corticopontine neurons)
• corticospinal neurons from cortex to spinal cord - innervate LMN in spinal cord

• CN3 gets 5/7 eye muscles
• eye movements - papillary constrictuon & accomodation, muscles of eyelid
• damage LMN, get droppy eyelid & large pupil
• patients can't look up, down, or medially, no pupillary light reflex
• damage VOR
• oculomotor nucleus in midbrain; edinger-westphal nucleus in midbrain

• innervates one eye muscle - intorsion, downward gaze
• lesion LMN, get head tilt, can't look downward
• trochlear nucleus in midbrain

• somatic sensation from face, mouth, cornea; muscles of mastication
• when lesion LMN - open jaw deviates toward side of lesion, atrophy of masseter muscles, can't feel on face
• trigeminal motor nucleus in pons
• trigeminal sensroy ganglion (the gasserian ganglion)
• trigeminal pain enters pons, descends to medulla then synapses & crosses midline 

• innervates one eye muscle, abduction or lateral movements
• lesion LMN, can't look laterally, eye with lesion just sort of looks at nose
• could happen with tumors in CSF in 4th ventricle
• damage VOR
• nucleus in midbrain

• innervates facial muscles
• controls muscles of facial expression, taste from anterior tongue, lacrimal & salivary glands
• with lesion of LMN, no closure of eye, no mouth refraction, no taste at top of tongue
• if have upper moton lesion, just weakness of inferior facial muscles (no eyebrow or forehead)
• if have LMN, weakness of superior & inferor facial muscles
• this is because the LMN of lower facial muscles are supplied solely by the contralateral motor area
• clinically, only the contralateral lower facial muscles are paralyzed after a unilateral lesion of the corticobulbar tract above the pons
• facial motor nucleus; superior salivatory nuclei in pons
• trigeminal (gasserian) ganglion

• hearing & sense of balance
• test vestibular function by assessing gaze fixation during head rotation, perform caloric test
• loss of vestibuloocular reflex
• loss of balance
• deafness
• spiral ganglion, vestibular (scarpa's) ganglion

• innervates ipsilateral tongue
• see atrophy of & deviation to side of lesion
• hypoglossal nucleus of medulla
• does tongue movements

• weakness or paralysis
• decreased superficial reflexes
• hypoactive deep reflexes
• less active tendon reflexes
• decreased muscle tone
• fasciculations & fibrillations
• severe muscle atrophy

• weakness
• spasticity
• increased tone
• hyperactive deep reflexes
• clonus
• babinski's sign
• loss of fine voluntary movements

• results from left capsular (internal capsule) lesion
• UMN, vascular damage
• head tilted
• paresis of lower facial muscles
• elbow flexed
• forearm pronated
• fingers flexed
• hip circumducted
• knee extended
• foot plantar flexed

• clasp knife - initial resistance to rapid stretch & then suddenly collapses as a resul tof excitation of tendon organs & their Ib afferent nerve fibers
• exaggerated patellar reflex
• clonus - on stretching the Achilles tendon, the brisk contraction of the agonists initiates a myotactic reflex in the antagonists & so forth, resulting in repetitive contractions
• Babinski - when touch bottom of foot, feet spread out and back instead of clench forward

• decerebrate = rostral midbrain to mid-pons lesion (includes red nucleus)
• decorticate = rostral to red nucleus
• Red nucleus facilitates flexors in upper limbs 
• with red nucleus cut (decerebrate), comatose patient has uppe rand lower limbs extended, can't cross them over
• without red nucleus cut (decorticate), comatose patient can cross arms - upper limbs flex & lower limbs extend

Neurological Diseases of LMNs and UMNs

disease can affect

• myopathies = muscle (usually proximal limb weakness)
• peripheral neuropathies = often sensory + motor symptoms
• neuropathies = neurons (usually distal weakness)
• fasciculations = twitches ~ neuronal (at terminal)

disease can affect

• neuron itself (ALS, SMA)
• axon of neuron (often demyelinating,eg CMT, GB, MS)
• neuromuscular junction (MG, LEMS)
• muscle fbers (lots of genes affected, esp dystrophin, but also channelopathies - MD)

Vestibular inputs

Vestibulospinal

• Vestibulospinal - from vestibular nuclei/ventromedial paths of UMN = control posture and balance; fibers to spinal cord, cerebellum, also to CN 3,4,6, to MLF (controls head position)
• vestibular inputs from CN8 to vestibular nuclei  (ventral to 4th ventricle) are important and project to spinal motor neurons via vestibulospinal tracts
• neurons from emdial vestibulospinal tract to innervate head, neck, & trunk muscles
• axial, posture, balance

• demyelination & leads to block of AP conduction
• peripheral nerve damage and see sensory (esp pain), motor and reflexes lost (LMN syndrome)
• PNS neurons can regenerate but quite slow so muscle can atrophy before neuron grows back
• Chronic: eg inherited mutations in myelin proteins, Charcot-Marie-Tooth, diabetes, VitB12 deficit
• Acute: eg. Guillain-Barre (GB) - after infection & can be mid or severe and see Abs to myelin

• Guillan-Barre disease
• acute acqured peripheral demyelinating

• Charcot-Marie-Tooth disease
• hereditary demyelinating
• motor & sensory

Basal Ganglia basics

purpose & anatomy

• caudate & putamen = striatum (combined in animal brains);inhibitory GABA-ergic interneurons 
• putamen & globus pallidus = lentiform nucleus (anatomical term)
• globus pallidus = output to thalamus
• external globus pallidus = lateral GP
• internal GP = medial GP
• substantia nigra & subthalamus in midbbrain
• basal ganglia control initiation of movements, precise, voluntary movements
• projects to UMN - no direct connection to LMN
• basal ganglia loops come from cortex
• nigrostriatal tract = DA fibers that degenerate in Parkinson's

• cortex -(glu)-> +
• medium spiny neurons in striatum (putamen) -(GABA)-> -
• GP internal/medial GP -(GABA-tonic)-> -
• thalamus -(glu)-> +
• motor/premotor cortex
• at rest, GP neurons release low level of GABA, os if inhibited they release less GABA
• activation to allow initiation of movement,
• allowing activity in UMN due to releasing thalamic neurons from tonic inhibition (disinhibition)
• substantia nigra activates direct pathway via D1 receptors on striatum so increases movement

• cortex -(glu) -> +
• medium spiny neurons in striatum -(diffuse projections)-> -
• GP external/lateral GP  -(GABA)-> -
•  subthalamus -(glu)-> +
• GP internal/GP medial -(GABAtonic)> -
• thalamus (VA nucleus) -(glutamate)> +
• motor
• Inhibition of unwanted movement
• substantia nigra inhibits indirect pathway via D2 receptors on striatum so removes it inhibition

• convergence of 100 striatal neurons on 1 GP neuron
• usually 1 straital axon sparsely contacts severalpallidal neurons then synapses densely on the dendrites of a particular pallidal neuron
• this integration allows for compariso & faciliates making a selection 8 comparison
• basal ganglia good at reproducing wanted motor pattern & inhibiting unwanted

• facilitate chosen motor movement
• direct pathway by releasing UMN from tonic inhibition
• suppress competing motor movements
• more diffuse indirect pathway which increases tonic inhibition of UMN

• tyrosine
• tyrosine hydroxylase is rate-limiting step
• also need DOPA decarboxylase to turn DOPA into Dopamine
• give L-DOPa for Parkinson's
• synthesized in substantia nigra & ventral tegmental area

• reuptake into (pre)synaptic terminals by DAT or NAT, remove DA/NE from synapse
• MAO = monoamine oxidase in mitochondria of presynaptic cell and extracellular forms too, breaks down
• COMT = catechol-o-methyl transferase in synaptic cleft and in pre- and post-synaptic cells (DA, NA, and adrenalin, not 5HT)

• medium spiny neurons (MSNs) that project to GP internal have D1 receptors with a Gs protein that activates adenylyl cyclase
• MSNS that project to GP external have D2 receptors with a Gi protein that inhibits adenylyl
• dopamine is thought to modulate the cortical inputs to MSNS, enhacning excitation via D1 receptors & negating it via D2 receptors

• MPPP = opiod analgesic, analog of Demerol
• DA neurons sensitive to oxidative poison MPP+ which is a breakdown product of MPTP, structure similar to paraquat
• MPTP produces a severe, permanent Parkinsonian syndrome & used to create animal models of PD
• awake rhesus monkey made Parkinsonian with MPTP and w/in seconds of subthalamic stimulation symptomss abated and pallidal cell discharge became more regular

Cerebellum

purpose, subdivision, & components

• NO DIRECT INPUT ON LMN
• cerebellum = precise/fine motor movments, flowing
• 40x fibers are going out of cerebellum as going in (modulating movments)
• anterior lobe = spinal cerebellum
• posterior lobe = cerebral cerebellum (cortical, motor learning)
• flocculonodular lobe = vestibular cerebellum (balance)
• inferior cerebellar peduncle = mostly input (climbing fibers from olives), letting cerebellum know about wrong movement
• middle cerebellar peduncle = all input (mossy fibers from pons)
• superior cerebellar peduncle = mostly output
• nuclei = receive inhibitory input from purkinjes & collaterals from climbing and mossy fibers; outputs leave cerebellum & excite brainstem and thalamus
• fastigial (center), interposed(more lateral), and dentate (most lateraal)
• fastigial & bilateral output affects posture, gait, and eye movements
• interposed and dentate and ipsilateral control of more distal muscles

• INPUT
• cortex -> pons -> posterior lobe ceerebullum (via middle cerebellar peduncle)
• OUTPUT
• dentate nucleus -> thalamaus (via superior cerebellar peduncle) -> cortex
• inflammation of 4th ventricle can cause its syndrome
• have ataxia, overshooting & pulling back, intentionaltremor, can't flip hands

• INPUT
• spinocerebellar tract and dorsal nucleus in spinal cord (2nd neurons from proprioceptors) -> cerebellum (via inferor peducle)
• also info to anterior lobe from trigeminal, RF, pontine nuclei
• OUTPUT
• via fastigial nucleus, vestibular nuclei, and RF and bilateral influence on head, neck, & proximal muscles
• influences more distal muscles via interposed, red nucleus, and RF
• B vitamin deficiency causes syndrome (often with spirits)
• causes shuffling/uncoordinated, clumsy movments of lower limbs

• INPUT
• ears -> vestibular nuclei -> cerebellum
• OUTPUT
• fastigial nucleus -> vestibular nuclei -> spinal cord (medial vestibulospinal tracts)
• syndrome caused by medulla blastoma - seen in children where they reel trunk from side to side and stand on wide base

• climbing fibers from inferior olive to Prukinjes and produce a complex spike
• mossy fibers synapse on lots of granule cells & on golgi neurons
• granule cells synapse on Purkinjes, stellate, and basket cells
• many simultaneous granule celss excite Purkinje to produce on simple spike
• glu in mossy fibers, climbing fibers, granule cells
• gaba in purkinje, golgi, stellate, and basket
• Purkinjes = GABAergic to inhibit cells incerebellar nuclei = output cells of Cerebellum
• LTD (change in response to parallel fibers within 200ms of climbing fiber spike)

• some diseasesof the cerebellum are due to mutations that cause aberrant cell migration
• Reeler = ECM mutation
• Weever = inward rectifier K+ channel
• cerebellar ataxias = progressive ataxia nad cerebellar loss - some dominate, recessive, and x-linked
• spinocerebellar ataxias = most are polyglutamine diseases (TNRE/CAG repeats in a variety of genes)
• SCA13 = point mutations in KCNC3 gene (paper we read)

• fast afferent fibers
• cell bodies in DRG
• APs propagate rapidly to spinal cord
• segemented into dermatomes (spinal nerves)
• specialized endings - fast and slowly adapting
• Merkel has very high spatial resolution
• enable mechanical stimulation to cause a receptor (generator) potential
• if receptor potential is sufficient enough for depolarization to reach threshold, then APs are fired along the sensory afferent

• fast afferents
• info about psition of body in space
• receptors = muscle spindles activated by muscle stretch, GTOs and activated by muscle contraction
• stretch reflex = muscle spindle is afferent, signals muscle stretch, synapses in spinal cord and activated LMN to cause muscle contraction and gamma motor neuronto contract muscle spindle fiber
• GO and signal muscle tension so get muscle relaxation
• wen contract a flexor have to relax the antagonist extensor muscle
• reflexes allow for muscle tone
• spinal cord circuitry can signal complex movements due to reflexes

• 1) periphery to medulla, ascends ipsilaterally 
• gracile = lower body; cuneate = upper body
• 2) medulla to thalamus (cross midline in medulla)
• first synapse
• 3) thalamus (VPL body/VPM head) to SS cortex 
• propoceptor pathways similar but more collaterals directly to LMN (like the knee jerk reflex) and to cerebellum (synapse in Clarke's nucleus and ascend via dorsal spinocerebellum). 

• 1) periphery to where it enters spinal cord
• 2) spinal cord to thalamus (cross midline in spinal cord & ascends in anterolateral area called spinothalamic tract)
• 3) thalamus to SS cortex
• from head, trigeminal pain enters pons, descends to medulla then synapses & crosses midline
• As well as sensory experience (via thalamus to SS cortex) pain also has emotonal, motivational, and cognitive aspects (to amygdala, hypothalamus, anterior singulate and insular cortices)
• stress can affect how we perceive pain

• pain neurons cell bodies in dorsal root ganglion
• Adelta = thin myelination = first pain
• C = unmeylinated = second pain
• Visceral pain = few nociceptor afferents and travel with afferents that detect somatic, cutaneous pain so can get referred pain
• our experience of pain can be affected by context and by descending analgesic pathways
• from amygdala, hypothalamus, medullary RF, locus coeruleus, raphe nucleus
• opioids particularly important - enkephalins, endorphins, and dynorphins all found in PAG.
• receptors in PAG, RVM, and dorsal horn
• enkephalin interneurons gate theory of pain (rubbing wound, TENS) - stimualte AB fiber/mechanoreceptor and activates inhibitor local circuit neuron and that inhibits the dorsal horn projection neuron
• descending pathways affect synaptic terminals of nociceptive afferents, excitatory and inhibitory interneurons, and projecton neurons

Nociceptive & mechanosensory pathways

& different kinds of lesions

• can localize lesion by where there is loss of pain and touch
• pain & temperature cross at spinal cord & touch crosses at medulla
• pain and temperature have 1st synapse in spinal cord & touch has first synapse in medulla
• so say there's a cut in left area of spinal cord
• the right side has a reduced sensation of temp and pain (contralateral)
• the left side has a reduced sensation of 2-point discriminaton, vibration, and proprioception (ipsilateral)
• there's also an zone on the left near the lesion where there's a complete loss of sensation (ipsilateral again)
• for head, trigeminal pain enters pons, descends to medulla, then synapses & crosses midline and eventually goes up to postcentral gyrus with face area at the ventral end
• thalamic or capsular lesion: contrateral heminanesthesia
• lateral medullary lesion: ipsilateral facial pain loss & contralateral limb pain loss
• spinal cord hemisection: ipsilateral touch loss & contralateral pain loss
• commissural syndrome: bilateral pain/temp loss at level(s) of lesion 

• NSAIDs = aspirin, ibuprofel, naproxen = good painkillers - block prostaglandin / thromboxane / leukotriene production - acts at inflammation. Adverse effects like stomach ulcer & liver toxicity
• opiates = narcotic sfrom poppy = best analgesic is morphine but have respiratory depression, constipation, dependence, tolerance, bad withdrawal effects; heroin abused, naloxone = antagonistl codeine, oxycodone,  & hydrocodone have lower potency at u receptors, Buprenorphine = partial Uu agonist; pentazocine = K agonist (use in obstetrics because lss respiratory depression in baby)
• cannabinoids = CB1 (cells of immune system) and CB2 (neurons) GPCRs, come clinical trials with and without opiods, adverse neurocognitive and psychoactive effects
• Trk A, anti-NGF (NGF acts with free nerve endings)
• capsaicin and TRIPV1 agonists = induce an analgesic effect following an initial excitatory resonse, used for post-herpetic, diabetic, HIV
• bradykinin antagonists

Peripheral Sensitization

Central Sensitization

• peripheral - lots cells and lots inflammatory molecules eg cytokines, bradykinin, prostaglandins
• NSAIDS like aspirin, ibuprofen blck COX & prostaglandin formation
• central - some LTP-like mechanisms in dorsl ahorn neurons & damage to these pathways may cause neuropathic pain

• glial activation participate sint he mediation of pain including neuropathic pain
• release of neuroexcitory, proinflammatory products by glia occurs in response to microglial and astrocyte activationincluding neuronal chemokines, neurotransmitters, neuromodulators

• sound causes movement of fluids in cochlea
• causes depolarization of hair cells (receptor potential) - movement of cilia opens ion channels
• caues neurotransmitter release onto and depolarization of CN8 which projects to the brainstem
• high k+ in outside of cilia, depolarizes in this case

• 1) cochlea -> brainstem (=CN8)
• 2) cochlear nuclei -> superior olivary nucleus (bilateral)
• 3) superior olivary nucleus -> inferior collculus
• 4) inferior colliculus -> medial geniculate in thalamus
• 5) MGN -> superior temporal gyrus = auditory cortex
• the superior olivary nucleus computes the location of a sound by interaural time diffrences (topographical representation of auditory space)
• auditory cortex has a frequenc y map

• semicircular canal s& utricles
• resonance in hair cells due to ion channels - more mechanical tuning in cochlea
• when move head, move stereocilia, & resoance frequency to how far you've moved

• 1) utricle -> brainstem (=CN8)
• 2) vestibular nuclei -> LMNs via lateral vestibulospinal or MLF & medial vestibulospinal tracts
• axial and proximal muscles for balance
• vestibuloocular reflex = move head but keep eye on one thing
• 1) ampulae -> brainstem (=CN8)
• 2) vestibular nuclei -> CN3, 4, 6, (LMN) via MLF (medial longitudinal fasciculus)
• head turns to right so eyes need to move left to maintaiin gaze
• need to contract lateral rectus muscle in left eye (CN6) and contract medial recuts muscle in right eye (CN3)
• vestibuloocular nystagmus = involuntary eye movements, use in coma, eyes move in other direction than move head; put cold or warm water i nears and track eyes

• myopia and refactive errors
• glaucoma - increased pressure, aqueous humor not drained and intra-ocular pressure damages optic nerve
• cataracts - loss of lens transparency, laser surgery now good
• retinitis pigmentosa - inherited XLRP, ADRP, ARRP, apoptosis of photoreceptor cells especially rods. Genes for phototransduction pathway mutated. See dark clumps of pigment

• rods = sensitive in low light
• cones = fine acuity and color, in fovea and center part has n RGCs or blood vessels (macular degeneration is degeneration around ovea)
• retinal pigment epithelium = melanin prevents light from scattering at back of eye, phagocytoses old photoreceptor discs and regenerates photopigments and recycles components also converts trans-retinal back to cis-retinal for phototransduction
• circuitry: rods/cones (hyperpolarized by light -> bipolar cells  (short neurons in retina with receptor potentials -> retinal ganglion cells (RGCs) = longneurons that project to thalamus so have APs

• rhodopsin = GPCR
• 11-cis etinal = molecule related to vitamin a (photopigment
• light activated rhodopsin, isomerizes cis-retinal to trans form and this activates transducin (G protein)
• active alpha subunit transductin activates cGMP PDE (phosphodiesterase)
• cGMP concentrations decrease
• closes Na+/Ca2+ channel
• hyperpolarizes cell and less NT released onto bipolar cells
• cones have slightly diffferent GPCRs & preferentially activated by red/blue/etc light

• RGCs respond maximally when a spot of light is shone in the center of a dark surround or a dark spot in the center of bright light 
• because looking at differences, why we see so many levels of light
• visual cortical cells respond maximally when a bar of light of a specific orientation is shone
• cerebral cortex has 6 layers of cells that run parallel to surface of brain
• LGN to layer 4 (lots of these in sensory systems) to layer 2/3 (where first VC cells respond to both eyes) to layer 5 (output)
• Electrode placed perpendicular will push through one column of cells that all respond to same orientation of light
• electrode placed parallel to surface and cells respond to differnt orientations of light (pinwheel organization)

• 1) bipolar cells to RGCs in retina (form optic nerve)
• 2) RGCs in retina to LGN in thalamus (optic tract and optic nerve), RGC from medial nasal retinas cros sin optic chiasm (right cortex to left visual field)
• 3) LGN to occipital cortex (primary visual) via optic radiations
• retina inverts image
• other pathways:
• hypothalamus to control day/night cycles
• pretectum for reflexes
• superior colliculus for orientation of head and eyes 

• depends on different proteins (opsins) being expressed in different cone cells,
• GPCRs - 7 transmembrance helices  - hold the retinal pigment molecules in diff positions so they preferentially absorb light of diff wavelengths
• opsin genes for red and green light are similar and on X chromosome
• normal people have on ered gene and 5 green genes

Pupillary Light Reflex

Pupillodilator Reflex

Accomodation Reflexes

• Pupillary Light Reflex 
• parasympathetic
• prtic nerves to optic tract to pretectum to edinger-westphal nucleus (parasympathetic cell bodies, ACh) and they bilaterally contrict both pupils
• shine light in one eye and both constrict
• Pupillodilator Reflex 
• sympathetic
• dilate pupils
• accident check to see if pupils are different size
• from dilator pupil to sympathetic chain to spinal cord to ypothalamus
• Accomodation Reflexes
• when move things closer, constrict pupil and medial muscles and get a thicker lens

• 1) tongue to brainstem (CN7, 9, 10)
• 2) nucleus of solitary tract (NTS) to VPM in thalamus
• 3) VPM to parietal operculum (primary taste cortex)

• papillae in tongue have taste buds
• sour = on side, ion channels, respond to protons
• sweet/umami = front and side, GPCRs (dimer of T1R2/T1R3 for sweet, dimer of T1R1/T1R3 for umami)
• salty = on frontand side, amiloride sensitive ion channel respond to Na+
• bitter = back, GPCRs (~30 genes) via Gq, PLC, IP3, & TRPM5
• GPCRs signal a cascade that involves activation of phospholipase C to release DAG and IP3, IP3 opents TRP Ca2+ channels

• 1) ORNS in olfactory epithelium (OE) to olfactory bulb (OB)
• 2) OB to orbitofrontal cortex, pyriform cortex & amygdala/uncus
• 3) amygdala to thalamus
• 4) thalamus to orbitofrontal cortex

• ORNs express specific odorant receptor proteins = GPCRs (400 functional genes in humans vs 1200 in mice)
• activate a G-protein and activate AC so cAMP increased and opens cAMp gated Na/Ca channels to open Calcium gated Cl- channels via CAMKII and depolarize ORN
• each ORN only expresses one type of receptor so responds to specific odorants
• axons from ORNs expressing a particular odorant receptor converge in specific glomeruli in olfactory bulb
• neruons from olfactor bulb project to olfactory cortex, amygdala, and other areas of the brain

• saccades = rapid, ballistic movements to foveate new targets
• smooth pursuit = slower movements, keep moving stimulus on fovea
• vergence = align foveas when objects different distance away (accomodation reflex)
• vestibulo-ocular reflex = maintains gaze while turning head
• optokinetic nystagmus = like VOR but works for slower movement = smooth pursuit of slow moving object followed by quick saccade in opposite direction

Reticular Formation

basics & inputs & outputs

• mesencephalic and rostral pontine reticular formation modulates forebrain activity/cortical activation, cell bodies of modulatory monoamine and cholinergic systems
• caudal pontine and medullary reticular formation for premotor coodination of lower somatic and visceral motor neuronal pools (coordinating LMN)
• inputs form sensory, cerebellary nuclei, and cortical UMN
• efferent output to LMN (mainly axial) of spinal cord and brainstem and visceral motor - gaze centers, sneezing, yawning, swallowing, and respiratory control centers
• reticulospinal neurons in rostral & caudal areas = innervate LMN medial
• inputs = cerebellum, cranial nerves, forebrain centers, anterolateral quadrant
• output = cerebral cortex (ascending RAS), integration of CN activation, spinal motor activity, pain modulatio, autonomic nuclei

Reticular Formation

NE, 5HT, DA, ACh

• NE = locus coeruleus project to thalamus, cortex, cerebellum, and down spinal cord - mood, arousal memroy, anxiety, attention, sleep-wake
• 5HT = in raphe nucleu projects to many areas (hippocampus, hypothalamus, thalamus, cortex, cerebellum, down spinal cord) and affect sleep-wake, mood, anxiety, aggression, drugs of abuse (ecstasy), pain control & analgesia - tryptophan to 5OH trptophan to 5HT with tryptophan hydroxylas as rate determining step
• DA = in substantia nigra pars compacta project to striatum for movement, DA in ventral tegmantal area project to nucleus accumbens, amygdala, pre=frontal cortex for reward pathways
• ACh = from brainstem and basal forebrain, dorsolateral pontine tegmentum (pons/midbrain junction) to thalamus - affects REM sleep-wake cycle, basal forebrain to cortex and hippocampus affects Alzheimer's

• anterior hypothalamic sleep center
• posterior hypothalamic arousal center
• locus coeruleus
• dorsolateral pontine RF, REM control center
• raphe nuclei
• solitary nucleus

• descending opioid pathways from PAG synapse on 5HT neuronsin raphe and NA neurons in locus coeruleus
• monoamine pathways then descend to the dorsal horn of the spinal cord to elicit analgesic effects
• local opioid interneurons

• olfactory - smell
• anosmia
• long axons go into CNS from nasal epithelium
• optic - vision
• blindness
• retina axons form nerve