Week 1 Lectures Flashcards
Why is gastrulation the most important stage in development?
All of the tissues in the body can be traced back to tissues formed at gastrulation
What are the terminal tissues formed by the ectoderm?
Skin and nervous system
Where do signals for differentiation of ectoderm into neural ectoderm come from?
Mesoderm - block BMP signaling and allow overlying cells to assume their natural identity
Wnt gradient
More wnt at the back end vs. front end –> anterior/posterior character
Neural plate
Initial thickening of ectoderm that grows cranial to caudal –> becomes concave after neural folds rotate into formation –>fuses at dorsal midline to form neural canal –> separates from surface ectoderm
Neural crest origination
forms from most lateral neuroectoderm –> squeezed out from both neural tube and overlying surface ectoderm
Neural tube closure defect - Spina Bifida
defect in vertebral arch formation or neural tube closure resulting in exposure and possible extrusion of spinal cord and meninges
Neural tube closure defect - Meroanencephaly
defect in tube closure resulting in the partial absence of the brain (most common nt defect)
Neural tube closure defect - Anencephaly
results in total absence of brain
Neural tube closure defect - Exencephaly
results in exposure and possible extrusion of the brain
Which supplement during pregnancy reduces closure defects by more than 50%?
Folic acid
The rostral end of the neural tube becomes what division of the brain?
Forebrain
The caudal end of the neural tube becomes what division of the brain?
Hindbrain
In which division of the brain do each of the ventricles form?
Forebrain-lateral, Midbrain-third, Hindbrain-fourth
What are the vesicles of the forebrain?
Telencephalon and Diencephalon
What is the vesicular name of the midbrain?
Mesencephalon
What are the two vesicles of the hindbrain?
Metencephalon and Myelencephalon
How many rhombomeres are there?
9 - subdivisions of the hindbrain
From what vesicle are the following structures formed? Olfactory lobes, Hippocampus, Cerebrum
Telencephalon
From what vesicle are the following structures formed? Retina, Epithalamus, Thalamus, Hypothalamus
Diencephalon
From what vesicle are the following structures formed? Cerebellum, Pons
Metencephalon
From what vesicle are the following structures formed? Medulla
Myelencephalon
The more wnt you have the more ______ the structure.
Caudal
What main gene is turned on in areas of low wnt?
otx2 transcription factor –> telencephalon to midbrain/hindbrain boundary –> anterior structures
What are the “crucial elements in executing the information from signals to the specificity of cells”?
transcription factors
What signal and corresponding gene control anterior/posterior patterning within the forebrain?
FGF signals from anterior telencephalon –> upregulate tf Pax6, downregulate tf Emx2 –> ratio of each gradient helps to determine identity of neurons in different regions of telencephalon along anterior/posterior axis
Hox genes
Homeotic transcription factors: DNA binding proteins that are expressed in the order in which they are expressed physiologically –> relating to segmental identity along anterior/posterior axis.
Three examples of anterior/posterior positioning.
- otx2 2. pax6-emx2 3. hox genes/rhombomere identity in hindbrain
A combinatorial code of ___________ defines rhombomere segmental identity even before the cranial nerves that will emerge are apparent.
transcription factors
What embryological structure induces the floor plate of the neural tube to relay dorsal/ventral patterning signals?
Notochord
What signal is released by the notochord and by the neural tube floor plate to induce ventral patterning?
Sonic Hedgehog (Shh)
What signal is released by the neural tube roof plate to induce dorsal patterning?
BMP4
What signal is released by the ectoderm to induce the neural tube roof plate to relay signals for dorsal patterning?
BMP4, 7
What extreme defect can loss of shh signaling components result in?
Holoproencephaly - defect in birfurction of the forebrain into two lobes resulting in a single holosphere
What pairs of genes are induced by the Shh gradient in dorsal/ventral patterning that also regulate each other in differentiation?
Dbx2-Nkx6.1 Pax6-Nkx2.2 Nkx = ventral
Intrinsic lineage
As cells arise they inherit their fate from parent cells.
Extrinsic determinants
As cells arise, they assume fates based on extrinsic determinants.
What mechanisms do cells derived from other cells employ to take on diverse roles?
Intrinsic lineage Extrinsic determinants
Where do the progenitor cells for the PNS come from?
Neural crest
What are the two main migration groups for neural crest cells?
Along surface ectoderm = non-neuronal melanocytes Ventrally = sensory ganglia, autonomic ganglia, and adrenal neuro-secretory cells
What identity do transplanted neural crest cells take on?
They take on the identity of the tissue where they ultimately reside
Neural crest cell fate is controlled by _______.
external cues
In the developing CNS, single progenitor cells make one/many different type(s) of neurons.
many
Inside-out maturation of the cortex (and type of cell involved)
Excitatory luminergic pyramidal-type cells: new neurons migrate past older layers of neurons to assume more superficial positions
Where are inhibitory cells generated?
(GABA neurons) - nascent striatum/lateral and medial ganglionic eminences –> migrate to the cortex/cortical sheet
Failure of GABAnergic neuron specification or migration can lead to lack of inhibitory interneurons in the cortex and the associated condition called ____________.
Epilepsy
What kinds of proteins are necessary for neuronal migration?
Tubulins and tubulin associated proteins
What condition is caused by Lis1?
Lissencephaly –> absence of folds and fissures on the surface of the brain
What defect can result in doublecorticin –> thicker cortex and improper migration?
Dcx microtubule defect
Which cells have axons that extend from the ventral surface to the pial surface?
Radial glia
The _________ is the motile structure at the tip of the neuron.
Growth cone
Conserved families of secreted and transmembrane molecules that influence axon trajectories are called _________.
Guidance cues
Two main types of signaling molecules/guidance cues
Chemotropic - can diffuse at a distance Contact - attached to the cell membrane or ECM Further divided into attractants and repellents
Axon guidance cue: Netrins
Chemoattractant secreted at ventral midline of spinal cord and stimulates axons to cross over
Axon guidance cue: Semaphorins
Chemorepellent - drive axons away from inappropriate target
Loss of the midline guidance cue receptor ______ perturbs crossing of interneuron axons in the fish brainstem.
Robo-3 - guidance receptor that determines whether an axon crosses at the midline
Disruption of robo-3 gene in humans induces what condition?
Horizontal gaze palsy - flattened medulla, enlarged 4th ventricle –> can’t look left and right b/c can’t coordinate the two eyes across the midline of the optic chiasm
EphrinAs are expressed at high levels in ______ and are ________ cues.
posterior tectum; repellent *only nasal retinal axons can reach posterior locations by expressing low levels of EphA receptor
EphB’s are expressed at high levels in ______ and are _________ cues.
ventral tectum; attractant *retinal axons with high levels of ephrinBs are drawn more strongly into the ventral tectum
Changing the size or activity of the muscle target controls the survival of motor neurons: about half of the motor neurons that are formed normally __________.
die by apoptosis - a superabundance of neurons are produced and half die off
Which family of proteins promote the survival of neurons from a development pool?
Neurotrophins
Neurotrophins interact with what kind of receptor?
Trk receptors
Sympathetic proprioceptive cells prefer which neurotrophin?
NT-3
Sensory neurons that go to the skin prefer which neurotrophin?
NGF
Post-synaptic cells secrete _________ that are required for neuronal survival.
trophic factors
What is the fate of secreted neurotrophins?
- act locally to affect growth cone motilty 2. can be transported retrogradely to the nucleus where they can ‘short circuit” cell suicide (e.g. Nerve Growth Factor)
What happens if a neuron does not receive an appropriate neurotrophic signal?
No retrograde transport –> no shortcircuit of suicide –> apoptosis
Which cellular process contributes to babies’ lack of coordination at birth?
incomplete myelination (among other activity-dependent processes like visual circuitry)
Anterograde transport: motor, materials
Fast: Kinesin; organelles vesicles, membranes Slow: Bulk flow; cytoskeletal and other proteins
Retrograde transport: motor, materials
Fast: Dynein; trophic factors, signaling molecules, endosomes, lysosomes
2 mechanisms to disrupt fast axonal transport
- lack of oxygen/disruption of mitocondrial oxphos 2. anticancer drugs that depolymerize microtubules –> neuropathy
At rest the membrane is more permeable to ____ than ____ and____. this is due to _______.
K+; Na+, Cl-; different electrical properties of their respective ion channels
Action potential conduction requires what kind of current flow?
Active through the channels and passive current within the shaft of the axon
The distance traveled by depolarizing current in an axon is dependent on what two properties?
Length constant and time constant
Where in an axon is the refractory zone?
The area of inactivated Na+ channels upstream of a propagating action potential
What are the roles of glial cells?
- regulation of cell migration and axon guidance 2. formation of BBB 3. trophic and insulating factors 4. modulation of synaptic function 5. injury response
From what germ layer are glial cells derived?
mesoderm
Which cells myelinate in the CNS?
Oligodendrocytes –> single cell wraps around multiple cell membranes
Which cells myelinate in the PNS?
Schwann cells –> single cell wraps around the membrane of a cell
Roles of myelination
- decreases capacitance of the membrane 2. concentration of channels in one area of membrane –> makes area more excitable
Charcot-Marie-Tooth is a ________ disorder caused by mutations in _____.
demyelination; PMP22: peripheral myelin protein 22 –> proximal limb weakness
Which ion drives the release of vesicles into the synaptic cleft?
Calcium
The decision to fire an action potential occurs at the site of presynaptic input in the ______ system.
PNS
How is action potential propagation different in the CNS than in the PNS?
- the transmitter may be excitatory or inhibitory 2. The outcome of signaling depends on location, type of receptor, and type of signaling molecule
The decision to fire an action potential in the ____ occurs at the axon hillock.
CNS
Myasthenic syndromes involve impaired _______.
endocytosis of neurotransmitters
Lambert Eaton myasthenic syndrom affects wht ind of channels?
presynaptic Ca2+ channels
Botulinum and tetanus toxins affect proteins involved in what process?
vesicle fusion
Synapses in the ______ are plastic throughout development and adulthood.
CNS
The primary neurotransmitter in the PNS is ______.
Acetylcholine
The probability of neurotransmitter release in the PNS is ______ times greater than that in the CNS.
10x
The axon hillock is described as a booster zone because _______.
the threshold for action potential propagation is low because of the concentration of channels
The larger the membrane time constant of the postsynaptic cell, the longer/shorter the presynaptic potential lasts and the greater the extent of temporal summation.
longer
Length constant is dependent on which two factors?
conductance of the membrane and shape of the cell
Most excitatory synapses in the CNS form at what location?
Spines on the dendrites
Wallerian degeneration in PNS
an evolutionary conserved program of axon destruction in response to insult or injury–> Schwann cells wait for macrophages to finish cleaning axonal debris and for the axon to return/regrow
What is the hallmark cellular event in response to a degenerating axon?
Change in the distribution of Nissl substance –> RER –> chromatolysis in axotomized motor neurons (lose all the Nissl signal)
Wallerian degeneration in the CNS
- very slow/poor degeneration and clearance –> microglia instead of macrophages 2. inability to clear the debris is in part what is preventing robust regrowth 3. neighboring neurons are often affected
4 factors that inhibit regeneration in the CNS
- inhibitory environment for growth - glial scar 2. inhibitory molecules present in CNS myelin - Nogo, MAG, Slit 3. low intrinsic growth potential of adult neurons 4. slow clearance
3 molecules that inhibit axonal regeneration
Nogo, MAG, Slit
Inhibition of what gene system has recently been shown to be effective in axonal regeneration?
mTOR
of cranial and spinal nerves
12 pairs, 31 pairs (8, 12, 5, 5, 1)
The tapered end of the spinal cord ends at ____.
L2 vertebra
Meninges extend to what level?
S2 vertebra
The space between L2 and S2 is used for what procedure?
Lumbar puncture
White matter
bundles of axons organized into tracts or fasciculi (wrapped by oligodendrocytes)
Gray matter
neuron cell bodies
Dorsal/posterior horns
remants of the alar plate –> the dorsal half of the functional neural tube –> sensory neurons
Ventral/anterior horns
contain motor neurons
Dorsal root
carries all sensory information into an individual spinal cord segment; derived from neural crest –> neurons that give rise to their axonal and dendritic processes outside the CNS –> cell bodies found in ganglia
Ventral root
motor; cell bodies of most roots are found in ventral horn (except for some autonomic cell bodies)
The neurons of the ventral horn have a direct/indirect synaptic relationship with corresponding ventral roots.
direct
Some/all of the incoming fibers from a dorsal root will synapse on sensory neurons in the dorsal horn.
some
T/F Nerve fibers entering the spinal cord via the dorsal roots are of similar size.
F
Different size axon fibers correspond to what measure?
conduction velocity
What 3 factors distinguish dorsal fibers from one another?
- fiber diameter 2. degree of myelination 3. sites of termination
If a dorsal root is classified using a roman numeral it is coming from a sensory receptor coming from _______.
Skeletal muscle - muscle spindles (Ia) and golgi tendon organ (Ib)
Proprioception
term used to describe muscle position sense
Roman numerals for dorsal roots
1 = heavily myelinated –> 4 = unmyelinated
If a dorsal root is not categorized by a roman numeral but rather by an alphabetic scheme, it is innervating a receptor in ______.
skin –> tactile/touch receptors (A-beta dorsal roots –> slightly less myelinated than 1a/b)
Medial division of the dorsal root
course medial to the dorsal horn and largely ignore its superficial layers
1a and 1b fibers synapse in the ______ horn and are involved in _______ contractions of skeletal muscle.
ventral; reflex
A delta and cfibers carry _____ and _____ modalities and synapse in the _____ horn.
pain and temperature; dorsal
Ventral roots are classified as
alpha or gamma motor neurons –> all the axons of these cell bodies leave in a ventral root and make skeletal muscle contract via a spinal nerve
Alpha motor neurons
neurons whose cell bodies are in the ventral horn and innervate skeletal muscle
Gamma motor neurons
cell bodies in the ventral horn and innervate one of the muscle receptors that are found in skeletal muscle (spindle) and alter the sensitivity of muscle spindle
C5-T1 and L2-S2 have large/small ventral horn.
large –> more space needed for plexi innervated by these groups (brachial and lumbosacral)
Topographic organization of alpha and gamm motor neurons
medial neurons innervate proximal muscles and lateral neurons innervate distal muscles in a limb
The most important tract that plays a role in making skeletal muscles contract voluntarily is ________.
the corticospinal tract –> cell bodies in motor cortex –> terminates in spinal cord
Voluntary contraction of skeletal muscle requires an interaction of how many neurons?
2 in series
Which neurons are involved in voluntary skeletal muscle?
upper motor neuron and lower motor neuron (alpha)
What net effect do upper motor neurons have on muscle stretch reflexes?
Inhibitory
Sidedness of skeletal muscle contraction pathway
UMN in primary motor cortex (precentral gyrus) –> corticospinal tract –> medulla-spinal cord junction (pyramidal decussation) –> contralateral lateral corticospinal tract –> contralateral LMN in ventral root–> contralateral muscle
decussation
oblique crossing of axons
How many neurons are required for general sensory pathways?
3: dorsal root ganglion receptor (1st order neuron) –> ipsilateral 2nd order neuron –> cross –> courses in a tract or lemniscus –> 3rd order contralateral thalamus neuron –> contralateral postcentral gyrus
2nd order neuron always crosses midline of body near ______.
cell body
Dorsal Column Pathway Medial Lemniscal System
three neuron pathway that is conveying proprioceptive and touch modalities to conscious levels of cerebral cortex –> 1st order neurons ignore spinal cord and form ipislateral fasciculi that course to 2nd order ganglia in medulla –> cross midline –> medial lemniscus –> VPL thalamus –> cortex
The upward continuation of the axons that run all the way up the spinal cord to the 2nd neurons are called ___________.
Fasciculi
Which fasciculus carries information from the upper/lower halves of the spinal cord to the medulla?
cuneatus (t5 and above)/gracilis (t6 and below)
Ventral posterior lateral nucleus
area of thalamus that receives communication from 2nd order nuclei in the medulla and transmit that information to specific cortical areas
Anterolateral system responds to what modalities in what kinds of cells?
Pain and temperature; A-delta and cfibers
Anterolateral System
dorsal root ganglion –> ipisilateral dorsal horn –> cross –> contralteral spinothalamic tract –> contralateral thalamic nucleus –> 3rd axons to cortex
The first axon carrying touch and vibration are long/short.
long
The first axon carrying pain and temperature are long/short.
short
What modalities are carried in the spinothalamic tract?
pain and temperature
The axon of the second neuron in sensory processing must do what?
Cross the midline of the CNS
What part of the brain is concerned with proprioception?
cerebellum
Spinocerebellar Systems
convey unconscious proprioception in ipsilateral tracts: dorsal spinocerebellar (lower limb) and cuneocerebellar (upper limb)
Autonomic pathways in the PNS use how many neurons?
3: pre and post ganglionic neurons + hypothalamic axons that synapse on preganglionic neurons
At what spinal cord levels do we find sympathetics?
T1-L2
Lesions in the neck at about T1 result in what condition? What about lesions in the brainstem affecting the same kinds of nerves?
Peripheral Horner’s syndrome vs Central Horner’s Syndrome
Which spinal cord segments control sphincteric function and micturition?
S2-S4
Preganglionic sympathetic signaling molecule is ________.
Acetylcholine
Postganglionic sympathetic signaling molecule is _______.
Norepinephrine
Dorsal spinocerebellar tract
dorsal root ganglion –> ipsilateral clarke’s nucleus in dorsal horn –> via the inferior cerebellar peduncle to cerebellar cortex
Cuneocerebellar tract
dorsal root ganglion –> ipsilateral 2nd order neuron in Brain stem –> via cerebellar peduncle to cerebellar cortex
Main sections of the spinal cord
- Dorsal = sensory (afferent) 2. Ventral horn = motor (efferent) 3. Intermediate = sensory motor circuits 4. Dorsal column = axons of large diameter mechano/proprioceptors
Spinal reflexes
involve incoming sensory information which will enter from spinal nerves to the dorsal horn (large diameter axons) and branches toward the brainstem and to the local spinal cord segment (synapse on motor neurons or on interneurons)
Muscle spindle organ is sensitive to what?
small changes in muscle length
Where are muscle spindle organs distributed?
in the main belly of the muscle; 10fold smaller than the associated skeletal muscle fiber; in parallel with the muscle fibers
Where are golgi tendon organs distributed?
clustered at the two musculotendonous junctions
What are golgi tendon organs sensitive to?
tension changes (muscle contraction)
Intrafusal muscle fibers
contained within the capsule containing spindle and are innervated by gamma motor neurons as opposed to alpha motor neurons which innervate everything outside the capsule
Two types of intrafusual fibers
- Dynamic fibers = initially stretch with skeletal muscle but secondarily relax –> respond to changes in length 2. Static fibers (majority) = stretch along with extrafusual fibers and hold the same length –> respond to maintenance of length
Dynamic intrafusal fibers contribute information about ________.
Rapid changes in length –> phasic length change
Static fibers provide information about ______.
the need to maintain muscle contraction to hold a position
Two types of innervation of muscle spindle
dynamic = 1 unique gamma neuron static = 1 unique gamma neuron + 1 generic group 2 sensory neuron *1 generic 1A sensory neuron wraps all the fibers in a muscle spindle
Striations in intrafusual muscles are limited to which region of the fibers?
the tips of the fibers –> regions that are contractile
Why is the central region of the muscle spindle devoid of striations?
contraction results in increase in tension in the central region that generates the signal for the spindle
Where are gamma motor neuron endings found in spindles?
At the edges of the contractile tips of the spindle where the contractile apparatus is
Where are sensory neuron endings found in spindles?
in the noncontractile central region
The transducing event in both muscular sensory organs is mediated by _________.
stretch responsive ion channels
T/F The 10-12 fibers within each golgi tendon organ are innervated by the same alpha motor neuron.
F –> enables the golgi tendon to monitor the tension in the muscle in a graded fashion
What kind of sensory neuron innervates the fibers of the golgi tendon organ?
sensory 1b axon –> enters capsule –> compression of tendon organ upon muscle contraction compresses tips of sensory neuron and this activates stretch-sensitive ion channels
Why is passive muscle stretch a bad way to generate action potentials at the golgi tendon organ?
the majority of the tension change is absorbed by the viscoelastic properties of the muscle belly, leaving little tension to affect the golgi organ
What factor contributes to the ability of skeletal muscle spindles to continue to be responsive to increases in length from a shortened position?
gamma motor neuron system
In slow movements, gamma neurons to what kind of muscle fibers are activated?
static fibers
In fast and uncertain movements, gamma neurons to what kinds of muscle fibers are activated?
dynamic fibers (as well as static gamma neurons in more controlled fast movements)
Golgi tendon organs have a linear/exponential response to muscle force.
linear
Cell bodies of all sensory neurons are located where?
dorsal root ganglion
All sensory neurons have excitatory/inhibitory effects on their target neurons.
excitatory
Reciprocal innervation
when sensory information comes into the spinal cord it will have two opposing actions for the muscles of a particular joint –> excitation of the alpha motor neurons + a parallel inhibition of alpha motor neurons to muscles with opposing force (e.g. extensors vs. flexors)
T/F spinal cord reflexes are under a lot of CNS regulation.
T
Why is the myotactic (stretch) reflex the fastest somatic reflex in the body?
- involves a single synapse in the spinal cord 2. the 2 neuronal components are fast conducting, large diameter
Myotactic stretch reflex pathway
patellar tendon tap –> stretch of the tendon –> 1A sensory neuron activation via muscle spindle –> synapse on alpha motor neuron –> excite alpha motor neuron in the same (homonymous) muscle –> activation; in parallel, 1A sensory neuron synapses on 1A inhibitory interneuron –> inhibit the activity of alpha motor neuron on opposite muscles
The golgi tendon organ reflex pathway
when there is an increase in alpha motor neuron activity to a contracting muscle –> 1B sensory neurons increase firing –> spinal cord –> excites two interneurons –> reduces homonymous muscle tension and increases tension on the opposing muscle
Why does the golgi tendon reflex involve muscles on either side of the joint?
To ensure feedback and prevent the movement from exceeding the goal
Withdrawal reflex
Ipsilateral flexion + contralateral extension (graded in intensity and follows reciprocal innervation rule)
Withdrawal reflex pathway
stimulus –> pain receptors (group 3 and 4) –> spinal cord –> excites ipsilateral flexion + inhibits ipsilateral extension of one leg + excites contralateral extension and inhibition of contraleteral flexion in opposite leg (to support the leg withdrawing from the stimulus)
T/F all sensory neurons end in the ipsilateral (to the side of their origination) side of the spinal cord.
T
Descending control of spinal reflexes comes from where?
Motor cortex (mostly) + somatosensory cortex –> corticospinal tract (axoaxonic presynaptic synapses near termination of sensory neurons)
Why does descending control signals of spinal reflexes synapse at the dorsal root termination of sensory neurons?
so that the sensory signal that has branched off before entry into the spinal cord is unperturbed by regulatory signals and can tell the brain exactly what happened at the muscle
T/F regulation in the spinal cord can reverse the activity of a neuron based on state (resting vs locomotion).
T –> different interneurons with different functions can be engaged in different states
PNS
any neuron that is at least in part, outside the CNS as well as associated glial cells and their effector cells (skeletal muscles) *diseases cause numbness and/or weakness
Diseases of the sensory neurons are called _______.
Sensory neuronopathy
Diseases of the motor neurons are called _______.
Motor neuronopathy
Diseases of the nerve roots are called _______.
radiulopathy
Diseases of the nerves are called _______.
neuropathy
Diseases of the neuromuscular junction are called _______.
myopathy
If both sensory and motor symptoms occur, what kinds of conditions might a patient have?
neuropathy or radiculopathy
Causes of sensory neuropathies
- toxins (e.g. cisplatin) 2. anti-Hu/ANNA1 antibodies (paraneoplastic syndrome) 3. Sjogren’s
Type grouping
Upon denervation of a muscle group, compensative fibers sprout from neighboring motor units in an attempt to renervate the damaged region. Because of this, large groups of neurons innervated by a single motor unit are found clustered instead of widely distributed as normal.
EMG findings in neuropathy
- Action potential amplitude doubles b/c of increased fibers/motor unit from renervation 2. Increased action potential duration 3. Decrease in the number of motor units in the muscle
EMG findings in chronic denervation
Denervated muscles have regular automatic firing at a low amplitude.
Amyotrophic Lateral Sclerosis (ALS)
relatively common disease; relentlessly progressive lost of motor neurons (no sensory involvement) –> begins in bulbar muscles, arms, or legs –> UMN findings –> idiopathic
Spinal Muscular Atrophy (SMA)
relentless progressive loss of motor neurons in babies –> 4 stages –> caused by loss of SMN1 gene
What gene results in an unstable transcript resulting in spinal muscular atrophy?
SMN2 gene
The intensity of spinal muscular atrophy is dependent on _______.
The proportion of unstable SMN2 transcript that is produced.
Herniation of the nucleus pulposus results in what condition?
radiculopathy AKA pinched nerve
What are the most common spinal levels involved in radiculopathy?
cervical (C7) and lumbosacral (L5)
Symptoms of neuropathies
- weakness and muscle atrophy 2. diminished/absent reflexes pain 3. sensory loss of large and small fiber modalities
Which kinds of axons are most affected by neuropathy?
long axons in distal places
T/F axons are the majority of cell volume.
T
T/F transport in axons could require years.
T
T/F energy failures anywhere in an axon could lead to failure of the whole axon.
T
Mutations in which dynein transport genes can cause spinal muscular atrophy and hereditary motor neuropathy 7B?
DYNC1H1 (dynein heavy chain 1) DCTN1 (dynactin)
Mutations in which kinesin transport genes can cause hereditary sensory neuropathy
KIF1A KIF5A
Mutations in what gene can cause syndromic inherited neuropathy?
TUBB3
Charcot-Marie-Tooth neuropathy is caused by duplication of what gene?
PMP22 –>overexpression and destabilization of myelin
Deletion of one copy of PMP22 results in what condition?
Palsy –> HNPP
The precipitating event at the NMJ is what?
AP causes calcium release which triggers vesicle release and fusion with the membrane
Which sodium gated channel propagates action potentials in skeletal muscle?
Nav1.4
What molecule is cleaved by botulinum toxin at the NMJ?
Snap25
What molecule do nerve gases bind to at the NMJ
AChE
What toxin blocks Nav1.4?
tetrodotoxin
Autoantibodies against alpha-P/Q calcium channels (in the NMJ) are found in what condition?
Lambert-Eaton Myasthenic Syndrome –> presynaptic –> decreased release of vesicles –> FLUCTUATING symmetric proximal weakness at rest (may improve during exercise due to increased calcium concentration with repetitive depolarization) *30% young women with specific HLA *70% secondary to paraneoplastic squamous lung cancer (diagnostic for the cancer)
In what condition are autoantibodies against ACh receptors in the NMJ found?
myasthenia gravis –> autoantibodies to receptor or MuSK –> lower response to the ACh
Safety Factor
The difference between the endplate potential and -50 mV is known as the safety factor –> most muscles in the body get enough ACh during a synaptic release to contract –> deficiencies can be presynaptic (not enough ACh) or postsynaptic (not enough receptors) –> “when the safety factor falls below 0, you go weak’
Increase in the amplitude of the compound action potential of the muscle is indicative of what kind of defect?
presynaptic –> residual buildup of calcium facilitates greater release of ACh all the way up to normal levels (100% release)
Decrease in the amplitude of the compound action potential of the muscle is indicative of what kind of defect?
postsynaptic –> pool of immediately releasable vesicles is depleted –> less ACh release and more failure of postsynaptic muscle –> normally this doesn’t happen because there is sufficient ACh released to stimulate the postsynaptic muscle
What constitutes a motor neuron pool?
many motor neurons, each of which innervates a motor unit with the muscle
Where are vesicles produced?
In NMJ, empty vesicles are made in the cell body (which for LMN is in the spinal cord) –> transported to the end of axons
Where are vesicles in the NMJ filled with neurotransmitter?
At the end of the axon –> ACh-H exchanger proton pump ensure inflow of ACh
T/F ACh is the only neurotransmitter to connect nerve and muscle.
T
T/F Vesicles made in the cell body have a higher pH than the cell body of the neuron.
F –> a lower pH ensures the ACh-H exchanger can function to fill the vesicle
3 stores of vesicles
- primary/immediate - 1000 vesicles at the presynaptic membrane 2. secondary/mobilization - 10,000 vesicles that can replenish the primary store 3. tertiary/reserve - 100,000 vesicles in the axon
T/F ACh is the neurotransmitter involved in the synapse between preganglionic sympathetic and parasympathetic neurons with corresponding postganglionic neurons.
T
What are the neurotransmitters employed in the junctions between postganglionic parasympathetic and sympathetic neurons and end organs?
ACh and norepinephrine
How do immediate store vesicles interact with the cell membrane?
nerve terminal has syntaxin and SNAP25, both t-snares that attach to synaptotagmin and synaptobrevin (vsnares) on the vesicle –> nsec1 dissociates from syntaxin allowing the bonds to form into a tertiary complex
3 main SNAREs involved in vesicle-membrane interaction
synaptobrevin (vesicular) + SNAP25 and syntaxin
To what molecule does calcium bind to trigger vesicle release?
synaptotagmin
T/F All immediate store vesicles are released upon activation.
F –> Under normal physiologic conditions, only 20% of primary store vesicles are released
T/F each ACh receptor binds 1 molecule of ACh
F –> each binds 2 which are both necessary for activation –> opening of selective cation channel
How many subunits form an NMJ nicotinic ACh receptor?
4
T/F the ACh receptor involve different subunits resulting in different receptor pathologies in different age groups.
T
Which associated ACh receptor protein is vulnerable to auto-antibodies?
MuSK –> muscle specific tyrosine kinase
Safety factor formula
resting membrane potential - stimulation (endplate potential) -30 = safety factor
Compound Muscle Action Potential
sum of voltage of muscle action potentials of all lower motor neurons stimulated at one time
Botulism - clinical presentation
fluctuating weakness from face that descends to limbs and respiratory muscles
How do tetanus and botulinum toxins differ?
Botulinum reduces vesicle release at the NMJ and tetanus toxin reduces vesicle release at inhibitory spinal interneurons
Organophosphorous Gases
synapse related –> reacts with AChesterase –> continual stimulation of receptor –> initial uncontrolled muscle contraction and subsequent paralysis (diaphragm)
Physostigmine, Neostigmine, Pyridostigmine
organophosphorous analogs that are reversible –> transient inhibition of AChesterase
In what NMJ condition does increased stimulation not prevent worsening of symptoms?
myasthenia gravis –> fluctuating skeletal muscle weakness/fatigue that worsens over time
Paralytics used in anesthesia
- Succinylcholine –> depolarizing NMJ blocker –> raises muscle contraction and subsequently induces paralysis 2. pancuronium –> selective competitive antagonist to ACh
2 types of synapses
- Electrical: fast, direct, all or nothing excitation via ion channels 2. Chemical: flexible, plastic, excitatory/inhibitory, amplifiable, via neurotransmitters in a cleft
Ionotropic transmission
ligand-gated ion channels: 1. excitatory = cation selective (Glutamate and ACh) 2. inhibitory = anion selective (GABA and glycine)
How is receptor diversity in ligand-gated ion channels generated?
different combinations of different subunits in the formation of the ion channel
Metabotropic transmission
g-coupled receptors: modulate synaptic input (amplifiable)–> different post-synaptic effects
Which kind of neuronal chemical transmission is faster?
ionotropic
Which kind of neuronal chemical transmission is more sustained?
metabotropic
How is receptor diversity in metabotropic receptors generated?
monomers but have different structural subtypes
Ex. 3 AA neurotransmitters
Glutamate, GABA ,Glycine
Ex. small molecule transmitter
Acetylcholine
Ex. biogenic amine neurotransmitter
Catecholamines, 5-HT, Histamine
Glutamate
major CNS excitatory neurotransmitter –> ionotropic and metabotropic –> reuptake by neurons and glia –> learning and memory
What are some excitotoxic effects of gluatamate?
seizures, hypoglycemia, ischemia, hiv
4 glutamate receptors
- NMDA - postsynaptic ionotropic gated with Ca and Na 2. AMPA - postsynaptic ionotropic gated with NA 3. Kainate - pre/post synaptic ionotropic gated with NA 4. mGluRs - pre/post synaptic metabotropic with increased PI hydrolysis and reduced cAMP
Glutamate NMDA receptor
- most common; slow and sustained currents -> minimal desensitization 2. permeable to Ca –> EPSP increase intracellular Ca that can act as second messenger 3. Glycine co-agonist 4. Mg plug –> blocks pore at hyperpolarized; open at depolarized
Glutamate AMPA receptor
primary mediator of fast response –> desensitize with repeated stimulation
Glutamate Kainate receptor
primary mediator of fast response –> desensitize with repeated stimulation
3 GABA receptors
main inhibitory transmitter in the brain (vs. glycine in the spinal cord) 1. GABAa - ionotropic (Cl) 2. GABAc - ionotropic (Cl) retina 3. GABAb - metabotropic
GABAa receptor
- principal mediator of fast synaptic inhibition in the brain 2. multiple subunits; gated with Cl- 3. allosteric modulators (benzodiazepine, barbituate, steroid)
How do benzodiazepines affect GABAa receptors?
increase the frequency with which the receptor opens
How do barbituates and steroids affect GABAa receptors?
increase affinity for GABA and increase channel conductance
GABAb receptor
- slow long lasting currents 2. metabotropic pre/post synaptic (K+ and Ca+) 3. baclofen treats spasticity, ecstasy, GHB
Acetylcholine
major excitatory transmitter in the PNS (but also widespread in the CNS) 1. ionotropic nicotinic receptor 2. muscarinic metabotropic receptor
Nicotinic acetylcholine receptor
ionotropic with neuron-type R –> expressed in the CNS early in life and decline with age
What kind of receptor is linked with Parkinson’s and Alzheimer’s disease?
Nicotinic and muscarinic ACh
Which systems do cholinergic systems regulate?
dopaminergic
Biogenic Amines
- serotonin –> both types of receptors; depression 2. catecholamines –> metabotropic (dopamine, norepinephrine, epinephrine)
Where is norepinephrine made?
locus coeruleus
Where is serotonin made?
Raphe nuclei
Where is dopamine made?
substantia nigra and ventral tegmental area
Where is acetylcholine made?
pontomesencephalotegmental complex, septal nuclei, and nucleus basalis
In the corticospinal tract, where do the fibers destined for the arms or upper limbs travel?
medially –> peel off and synapse with LMN earlier (remember, the corticospinal tract is on the edge of the spinal cord
In the corticospinal tract, where do the fibers destined for the legs or lower limbs travel?
laterally
Where do spinothalamic tract axons cross?
in the ventral white commisure near their level of entry
Where do spinothalamic tract 2nd order axons terminate?
in the contralateral ventroposterolateral thalamus
In what tract do spinothalamic tract 1st order axons travel before synapsing in the dorsal horn?
Lissauer’s tract
Where do axons from the nuclei gracilis and cuneatus terminate?
in the ventroposterolateral thalamus
In the dorsal column system, where do 1st order axons run?
in the ipsilateral fasciculi gracilis and cuneatus
Which spinal tracts cross in the lower medulla?
The medial lemniscal/dorsal column and the corticospinal/motor tract
Where do sympathetic fibers run?
ipsilaterally to the T1-L2 spinal nerves
Horner’s syndrome symptoms
ptosis, miosis, anhydrosis
Where do sympathetic fibers arise?
hypothalamus
What is the effect of cocaine on the eye?
blocked reuptake of norepinephrine –> makes the pupil large (unless sympathetic system is interrupted)
Where are afferent cell bodies related to bladder control located?
stretch receptors in smooth muscle wall of bladder send sensory input via S2-S4 dorsal roots
Where are efferent cell bodies related to bladder control located?
cell bodies in gray matter of S2-S4 –> parasympathetic stimulation causes contraction of detrusor
Where do parasympathetic axons controlling bladder function arise?
pontine micturition center
What happens once parasympathetic axons involved in the bladder response are myelinated?
you gain control over bladder emptying
Where do corticospinal axons cross?
- 90% at the pyramidal decussation –> lateral corticospinal tract 2. continue as anterior corticospinal tract and decussate in anterior white commissure near level of termination
What is the consequence of a lesion above the pons on bladder control?
infantile bladder (fill/empt cycley)
What is the consequence of a lesion above the conus and below the pontomesencephalic micturition center on bladder control?
acute: acontractile bladder chronic: spastic bladder secondary to loss of inhibitory influence on the detrusor –> incontinence
What is the consequence of a lesion of sacral dorsal roots, cauda equina, and conus medullaris on bladder control?
atonic bladder, flaccid, loss of sensation (dribbling)
What is the blood supply of the spinal cord?
Anterior 2/3 = anterior spinal artery from vetebral artery Posterior 1/3 = paired posterior spinal arteries
What is the watershed zone of the spinal cord?
midthoracic region –> least vascularized and vulnerable to infarct
What is the largest branch of the posterior artery system?
Artery of Adamkiewicz (T9-T12)
Slowness and stiffness are symptoms of UMN/LMN.
UMN –> increased tone/spasticity, hyperactive reflexes, pathologic reflexes
Weakness and cramps are symptoms of UMN/LMN.
LMN –> weakness, atrophy, fasiculations, decreased tone, decreased reflexes
What term refers to the loss of sensation at or below a dermatome?
sensory level
What term refers to loss of sensation in adjacent dermatomes with preservation above and below that level?
segmental sensory loss
Weakness in the extensors of the arms and the flexors of the legs indicate UMN/LMN.
UMN
- Motor: loss of all motor function below lesion
- Sensory: loss of all modalities below lesion
- Autonomic: bowel and bladder dysfunction
- Causes: trauma, compression, inflammatory myelitis
- Outcome:
- C1-C3 = ventilatory support
- C4 = partial ventilatory independence
- spared C7 = independent elbow –> live on own
T/F Bowel and bladder control can be lost with unilateral spinal cord injury.
F. Requires bilateral injury
- Motor:
- ipsilateral weakness below lesion
- segmental LMN and sensory signs
- Sensory:
- contralateral loss of pain/temp –> 1/2 levels below lesion
- ipsilateral proprioception loss below lesion
- Causes: trauma or compression by extrinsic lesion/rare intramedullary lesion
- Motor: anterior horn cells at the level of lesion with LMN findings
- Sensory (first affected): crossing fibers of spinothalamic fibers –> bilateral capelike loss of pain/temperature
- Autonomic: no bladder/bowel dysfunction
- Causes: syringomyelia (assoc. with Chiari malformation, congenital, or tumor), hematomyelia, intramedullary tumor
Chiari malformation
congenital malformation leading to partial herniation of the cerebellar tonsils through the foramen magnum that may be isolated or associated with syrinx or more severe malformation –> Central Cord Lesion
- Sensory: vibration/proprioception –> sensory ataxia that is worse in the dark –> + Romberg sign
Syphilitic posterior column syndrom/tabes dorsalis
- “great imitator”
- lancinating pains in legs
- no leg reflexes
- sphincter dysfunction
- blindness from optic atrophy
- deficits irreversible with penicillin
- Motor: spasticity and hyperactive reflexes with Babinsky sign
- Sensory: loss of proprioception and vibration –> sensory ataxia and + Romberg
- Causes: B12 deficiency
- Motor: LMN findings at affected segment
- atrophy
- fasciculations
- weakness
- Causes: SMA, Polio, WNV, Entero 71, Coxsackie A/B, Echovirus, Monomelic amyotrophy (benign)
- Motor: UMN and LMN findings (not visible on MRI)
- Motor: initial flaccid weakness below lesion but spastic chronic parapersis (corticospinal) + LMN abnormalities at the level of the lesion
- Sensory: loss of pain and temperature sensation below the lesion
- Autonomic: loss of bowel and bladder control
Intramedullary lesion
- initial symptoms reflect parenchymal damage –> involvement with segmental sensory and motor findings too –> leading to complete cord compression
- ex. ependymoma, astrocytoma, glioblastoma, myelitis, abscess
Intradural extramedullary lesion
- initial symptoms are extraparenchymal and may reflect root compression –> LMN symptoms
- increasing tumor size –> myelopathy
- schwannoma and meningioma
Extradural lesion
- initial symptoms extraparenchymal –> reflect root compression –> later myelopathy
- disc disease, epidural metastasis, primary bone tumor, lymphoma, epidural abscess
Most common herniations
- C7 –> Cervical Myelopathy
- L5 –> LMN lesion compressed nerve roots
- dermatomal sensory loss
- depression of reflexes at affected level
- radicular pain
- no bowel/bladder involvement
T/F You can have a cord syndrome with disc herniation at L5.
F –> cord ends at L2
Findings in Mild Cord Compression
radicular symptoms (e.g. touch hypersensitivity, pain in opposite limbs, girdle sensations, pain increased with coughing)
Findings in Moderate Cord Compression
ipsilateral UMN findings (spasticity and plantar extension) + contralateral pain/temperature loss
Findings in Severe Cord Compression
complete cord transection
Absent reflexes and muscle atrophy suggest UMN/LMN.
LMN
The presence of prolonged distal motor latencies and slowed conduction velocities is most consistent with what kind of neuropathy?
Demyelinating
Loss of motor amplitudes with sparing of conduction velocities is most consistent with what kind of neuropathy?
Axonal
Anterior horn cell abnormalities tend to spare what organ?
eyes
Normal nerve conduction studies, normal EMG, and abnormal repetitive stimulation studies localize a lesion to what?
NMJ
T/F A normal CK level rules out myopathic disease.
F.
In what conditions are NCS abnormal?
Peripheral nerve and sometimes NMJ
In what conditions does an EMG demonstrate fibrillation?
Peripheral nerve and anterior horn cell
T/F approximately 40-50% of mass of the adult human body is composed of muscle tissue.
What is the origin of the muscles of the limb and body?
The somite
Muscles of the back arise from which lip of the dermamyotome?
medial lip = epaxial muscle
Muscles of the back arise from which lip of the dermamyotome?
later lip = hypaxial muscle
What are the two most important signals in somite division and differentiation?
Wnt and Shh
Muscle of the head (but not the tongue) arise from what?
pre-chordal mesoderm
Which muscle receptor acts as a voltage sensor?
the dihydropyridine receptor
Which muscle receptor undergoes a confromormational change to release calcium upon voltage changes?
ryanidine receptor
T/F There is no active muscle breakdown or ongoing regeneration in congenital myopathies.
T –> they are not muscular dystrophies and can show clinical improvement and/or stable course
4 classical congenital myopathies
- nemaline myopathy
- centronuclear/myotubular myopathy
- central core disease
- multi/minicore myopathy
T/F congenital myopathies are degenerative.
F –> this would be a muscular dystrophy
What are red staining inclusions in muscle called in relation to congenital myopathy?
nemaline rods –> threads in the muscle
What are the two most important genes implicated in nemaline myopathy?
- Nebulin
- Actin
All genes related to nemaline myopathy have to do with the thin filament.
T/F All nemaline myopathy genes are to do with the thin filament.
T
3 key histological findings in muscular dystrophy
- degeneration
- regeneration
- connective and fatty tissue infiltration
Why are smooth muscle and cardiac muscle spared in nemaline myopathy?
different structure and isozymes related to the thin filament
During skeletal muscle regeneration, why does the nucleus move to the center of the cell?
b/c satellite cells fuse with the muscle to make up losses
Duchenne muscular dystrophy
- 1:3500 boys
- 2-4 year onset
- wheelchair <12 years
- lifespan now into 3rd decade
- proximal progressive weakness, pseudohypertrophy, elevated CK
- complications of cardiomyopathy, respiratory insufficiency, scoliosis
T/F Duchenne muscular dystrophy is x-linked.
T
Why do some muscles appear grossly larger in Duchenne’s?
- hypertrophy of remaining fibers
- infiltration of fatty tissue and connective tissue
What clinical sign is used to demonstrate proximal muscle weakness?
Gowers’ maneuver
What clinical sign demonstrates hip abductor weakness?
Stair climb with Trendelenburg sign
3 important late complications of Duchenne’s
- scoliosis
- respiratory insufficiency
- cardiomyopathy
Becker muscular dystrophy
- 1:30,000 males
- variable onset and severity
- wheelchair >15 years
- CK elevated
- cardiomyopathy still important (even when pt is ambulant)
T/F Only the full-length form of dystrophin can prevent muscular dystrophy.
T
T/F Duchenne’s is associated with increased autism risk.
T
What does dystrophin do in the muscle?
- dystrophin holds the muscle protein complex to the membrane –> when dystrophin is malfunctioning, the muscle complex will not function
Revertant fibers
muscles in which dystrophin is restored by a somatic mutation in the reading frame
T/F Most mutations in dystrophin are deletions.
T
What kinds of deletions are most common in DMD?
out of frame deletions –> truncated and degraded protein
What kind of deletions are most common in BMD?
in frame deletions –> preservation of reading frame
Frame restoration
removable of extra exons to turn DMD into BMD as a therapeutic approach
Which gene therapy vector is being studied for therapy of DMD and what is its main limitation?
Recombinant Adeno-associated virus –> has a size limit for the genes that can fit inside it
Where is CSF found in the CNS?
Ventricles and subarachnoid space
What color is blood on a CT?
white
What color is CSF on a CT?
black
What color is bone on a CT?
white
In an axial T1 MRI, what color is CSF?
black
In an axial T2 MRI, what color is CSF?
white
