Term
| what is the neuron hypothesis? |
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Definition
| all neurons have common morphologic features (cell body, axons with which they communicate) - reflecting their role as a communication system |
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Term
| what are the cell components important in degeneration/regeneration? |
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Definition
| microfilaments, neurofilaments, microtubules, RER, basement membrane, mitochondria, trophic factors, and cytokines. |
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Term
| what is the cytoskeleton of nerve cells composed of? |
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Definition
| microfilaments (7 nm actin subunits), neurofilaments (~10 nm intermediate fibers), and microtubules (~24 nm tubules of tubulin dimers). silver impregnation techniques were first used to show these characteristic neurofibrils, currently Ab are used for visualization. |
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Term
| what characterizes the microfilaments? |
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Definition
| these are composed of actin and compose the cell cortex - giving the cell its shape |
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Term
| what characterizes the neurofilaments? |
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Definition
| these intermediate nervous system filaments have a rod (core domain), carboxyl tail domain, and amino terminal head domain (heads and tails interact to create "cables"). they are composed of the heteropolymers: NF-L, NF-M, and NF-H (low-high, based on molecular weights). the number of neurofilaments correlates to the axonal diameter and these filaments are transported by slow axonal transport (1mm/day). the neurofilaments provide the framework of maintaining the shape and stability of the neuron, especially the axons. |
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Term
| what characterizes the microtubules/neurotubules? |
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Definition
| these tubular structures are composed of tubulin dimers and form tracks upon which transport takes place (perikaryon -> axon). there are 2 main types of transport in nerve cells: fast axoplasmic/anterograde (mainly for NT, uses kinesin+other motor molecules which bind to vesicles and move them at 200 mm/day) and slow axoplasmic/anterograde (mainly for structural/support proteins, 1 mm/day - allows for *synaptic plasticity esp in hippocampus). [anterograde: from cell body to axon/retrograde: from axon to cell body (200 mm/day)] |
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Term
| what are microtubule associated proteins (MAPS)? |
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Definition
| proteins such as tau proteins which help in moving organelles along microtubules and cross-linking microtubules to one another (can become hyperphosphorylated/modulated and accumulate in neurodegenerative disease). |
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Term
| what is the perikaryon, how is it studied? |
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Definition
| usually the cell body, which is studied classically via the nissl method - relies on use of basic aniline dyes (cresyl violet) which collectively stains (acidic) AAs in the nucleus and nissl substance (nissl bodies - RER). this will tell you if the cell is in a normal or pathologic state (based on presence of change). |
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Term
| what characterizes nissl substance/RER in different neurons? |
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Definition
| in motor neurons, there is a larger presence of nissl substance than in sensory neurons (motor: more NTs generally). the activity of the cell, such as functional stress and/or axonal injury/section dictates appearance - will disintegrate under these conditions (chromatolysis). |
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Term
| what is a retrograde cell reaction? |
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Definition
| ER/mitochondrial swelling of nerve cells and nuclear displacement to the periphery. |
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Term
| is chromatolysis reversible? |
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Definition
| yes, if there is regeneration of the cell |
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Term
| what is wallerian degeneration? |
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Definition
| damage to an axon which occurs both distal and proximal to the site of injury. damage too close to the cell body (at the axon hillock) will result in cell death. the extent of damage determines how well a cell can recover and crushing is more likely to regenerate than severing. |
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Term
| where in the nervous system is the basement membrane seen? extracellular matrix (ECM)? |
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Definition
| only in the PNS, but there is an ECM in both the PNS/CNS. in the PNS, BM surrounds all nerve fibers (membrane is continuous over all schwann cells) and in the PNS/CNS, chondroitin sulfate proteoglycans (CSPGs) exist as a part of the ECM (major determinant of cell regeneration). CSPGs are important for neurite outgrowth in development, but inhibitor in damage and aging - thereby reducing plasticity. |
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Term
| how does myelination occur in the CNS/PNS? how does this affect damage repair? |
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Definition
| in the CNS, oligodendrocytes can myelinate many individual axons while in the PNS only one schwann cell can myelinate an individual axon. damage in the PNS causes degradation of the myelin and the damaged part of the nerve cell w/a lot of macrophage activity = better recovery than in CNS (less macrophage activity, less clearance, and delayed remyelination). |
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Term
| what characterizes the role of mitochondria in the nervous system? |
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Definition
| there is a great demand for ATP in the nervous system to maintain polarizing gradients and metabolism. damaged mitochondria can produce free radicals which interfere w/oxidative phosphorylation (as can exogenous toxins and tissue ischemia) and mitochondrial DNA mutations (seen in normal aging) may result in less ATP production. |
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Term
| what is the effect of the synthetic toxin MPP+ on the mitochondria? |
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Definition
| MPP+ damages complex I of the mitochondria -> ROS -> lewey bodies (parkinsonism) |
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Term
| what regions of the brain are most at risk for mitochondrial damage? |
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Definition
| the putamen, temporal, and frontal cortex |
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Term
| what are some of the neurotrophic factors? |
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Definition
| these factors are very important in keeping the cell healthy, they include: *GDNF: glial cell derived neurotrophic factor (essential for noradrenergic innervation of the hippocampus from the locus coeruleus and maintenance of dopaminergic neurons in the substantia nigra), *FGF (fibroblast growth factor: promotes neuronal stem cell populations) and *EGF (epithelial growth factor: promotes differentiation of stem cells into glia in adult rat olfactory bulbs). these neurotrophins have been found to be very important for remyelination in MS (need to restore myelin for 2 reasons: conduction velocity and protection of the axon) and also in the healthy CNS: proliferation, survival, and regeneration of oligodendrocytes and their precursors. |
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Term
| what is growth associated protein 43 (GAP-43)? |
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Definition
| GAP-43 is expressed during growth in the CNS/PNS and in regeneration of the PNS. GAP-43 is not associated in normal retinal ganglion cells (RGCs), however if the optic nerve is cut close to the cell body (proximal axotomy), GAP-43 is expressed. GAP-43 expression also lasts longer if an intravitreal peripheral nerve graft is placed close to the cell body. |
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Term
| what is the role of cytokines in the nervous system? |
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Definition
| cytokines function as mediators/inhibitors of neurodegeneration which are induced in response to cell injury. TGF beta is neuroprotective, TNF alpha contributes to neuronal injury, and IL-1 mediates ischemic, excitoxic, and traumatic brain injury (acts on neurons, glia, and endothelia via Ca++). [last 2 are related to inflammation] |
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Term
| what are the acute and chronic responses to neuronal damage? |
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Definition
| acute: rapid, local degeneration of the axon and myelin sheath which is walled off: seal and swelling. chronic: glial response via phagocytic astroglia and microglia which try to remyelinate (delayed in CNS). |
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Term
| what characterizes the effect of axotomy on specifically the dorsal root ganglion/spinal motor neurons? |
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Definition
| chromatolysis occurs 2-3 days after injury and lasts 1-3 wks w/a massive regenerative protein synthesis response. different neurons types will exhibit different responses. |
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Term
| what is terminal neuronal degeneration? |
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Definition
| degeneration of an axon terminal of a distal segment. synapses will disappear in 2 wks |
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Term
| what is wallerian neuronal degeneration? |
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Definition
| the distal axon segment itself (not the terminal) degenerates 1 wk after degeneration of the axon terminal |
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Term
| what is transsynaptic (transneuronal) neuronal degeneration? |
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Definition
| neuronal degeneration of neurons which synapse upon or receive synaptic contacts from other degenerating cells (neurons downstream/upstream from damaged neurons atrophy). |
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Term
| what is excitotoxic neuronal degeneration? |
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Definition
| neuronal degeneration 2/2 to exposure of neurons to high levels of excitatory amino acids (damaged cells lose ability to make ATP, mitochondrial damage cause channels to be dysfunctional). |
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Term
| what characterizes wallerian degeneration in the PNS? |
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Definition
| neuropilins (NP-1/2: coreceptors for axonal guidance molecules sema3a/3f and VEGF) play prominent roles along w/their ligands in axonal pathfinding, fasciculation, and blood vessel formation during PNS development and in combating wallerian degeneration in the PNS (not necessarily seen in the CNS). |
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Term
| what characterizes the consequences of damage to unipolar, bipolar, and neurons recieving multiple inputs? |
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Definition
| unipolar: if cleaved, something will occur downstream. bipolar: may lose some, but not total function. more than one input: functionality maintained. |
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Term
| what are the different types of PNS injury? |
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Definition
| *chronic axotomy: a prolonged (> 1 mo) period where injured neurons remain w/o targets during axonal regeneration. *chronic denervation: the distal nerve stump is maintained by schwann cells w/o being reconnected to the proximal nerve (which is why rapid limb reconnection is sometimes possible). both will result in reduced numbers of motoneurons that regenerate their axons. to counteract, brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF) are used in low doses. |
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Term
| what characterizes DM neuropathy? |
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Definition
| this is a result of hyperglycemia-induced local metabolic and microvascular changes, leading to slower impulse conduction, axonal degeneration, and impaired regeneration. DM neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves = improper locomotor and visceral organ functions. neuropoietic cytokines may have a very important role through pleiotropic effects on glia and neuron homeostasis - esp: IL-1, IL-6, TNF alpha, TGF beta, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) [both good and bad]. |
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Term
| what characterizes excitotoxic neuronal injury? |
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Definition
| this occurs due to oxygen/glucose deprivation (ischemia keeps glutamate from being removed from cells, which leads to apoptosis) and results in swollen dendrites and irreversible damage if unchecked. |
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Term
| what characterizes neuronal regeneration in the CNS? |
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Definition
| gliosis: proliferation of fibrous astrocytes to form a glial scar, which is a barrier to collaterals which sprouts from the degenerating neuron. this can be overcome if the regrowing axons are helped to bypass the site of the lesion. |
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Term
| what characterizes neuronal regeneration in the PNS? |
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Definition
| a connective tissue sheath can support regrowth if it remains intact and cell bodies do not die, therefore reinnervation of the target organ is possible. |
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Term
| what are some molecular determinants of axonal growth and regeneration? |
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Definition
| the myelin-associated neurite outgrowth inhibitors: chondroitin sulfate proteoglycans, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and nogo A. the nogo-66 receptor is an integral membrane protein which localizes in the CNS myelin (not PNS), which if neutralized allows enhanced axonal regeneration and functional recovery following CNS injury as well as increased plasticity in uninjured CNS fibers. blocking EGF in the CNS has also been shown to promote CNS system regeneration (antiCA drug tarceva does this). (in the CNS, receptors of nogo and EGF may be acting in concert to prevent a regenerative capacity). |
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Term
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Definition
| if the gap between the proximal and distal stump of a severed peripheral nerve is too great, the growing axonal tips will not be able to cross the scar, and the sprout+scar tissue may form a painful neuroma. to prevent this, the severed nerve ends should be placed as close to each other as possible (w/help from nerve transplant which provides guiding schwann cells) in sx. |
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Term
| where does neurogenesis take place most successfully in the brain? |
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Definition
| in the more plastic areas: hippocampus and the submarginal zones around the ventricles (just below the ependymal cells). these areas have more stem cells. it is thought that more creative activities allow for higher neuronal regeneration potential. |
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Term
| what factors influence neurogenesis? |
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Definition
| high blood levels of glucocorticoids inhibit adult neurogenesis, NTs which stimulate granule cells to fire also inhibit stem cell proliferation in the hippocampus, and stress reduces stem cell proliferation by increasing excitatory NTs in the brain and secretion of glucocorticoids from the adrenals. |
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Term
| how can weakened or paralyzed extremities due to stroke be promoted to faster recovery of function? |
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Definition
| by inhibition of use in the unaffected side |
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Term
| what is keratin sulfate proteoglycan (vs chondroitin)? |
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Definition
| a special type of proteoglycan is made in the extracellular matrix surrounding the mossy fibers in the dentate gyrus (hippocampal formation) which allows for regeneration of mossy fibers. phosphacan, which is made by astrocytes is the only protein known to contain KSPGs - but it is only found in the CA3 region of the hippocampus. |
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Term
| what is the association between NO synthase and neuronal regeneration? |
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Definition
| NOS expression is highest following proximal axotomy (vs distal) and the higher the level, the greater the neuron loss. NOS inhibitors and NMDA receptor inhibitors promote survival of injured clark's nucleus neurons in the spinal cord. (NO reactive molecule and can form into peroxynitrites that damage membranes) |
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Term
| what is the association between complement production in nerve regeneration in the CNS and PNS? |
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Definition
| in the PNS, local production can maintain the health of a nerve (complement is produced due to injury = opsonization/binding onto the damaged material). in the CNS, even if complement is produced, you are not getting an opsonized event occurring fast enough to give you clearance of that material = nerve cell loss. |
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Term
| what characterizes neuronal degeneration seen in huntingtons? |
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Definition
| CAG repeats cause too many glutamines, huntington protein is made and cleaved into toxic fragments that accumulate in the nucleus of the cell bodies of the caudate nucleus = destruction of the caudate nucleus. |
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Term
| what characterizes neuronal degeneration seen in prion disease? |
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Definition
| accumulation of prion protein = amyloids = spongiform encephalopathy (kuru). |
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Term
| what characterizes neuronal degeneration seen in alzheimers? |
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Definition
| tau filaments accumulate as neurofibrillary tangles (overactivity of transglutaminase/underactivity of isopeptidase) and nerves lose the ability to communicate between the cell body and synapse |
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Term
| what characterizes neuronal degeneration seen in parkinsons? |
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Definition
| alpha synuclein accumulates in lewy bodies |
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Term
| what are the tx protocols for neurodegeneration? |
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Definition
| 1) neurotrophic factors (CNTF, NGF [nerve growth factor], FGF). 2) excitatory amino acid antagonists (kynurenic acid - endogenous antagonist of excitatory receptors). 3) gene therapy: in vivo - vector based implants, ex vivo - cells manipulated, then transformed. |
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