Neuronal Degeneration and Regeneration Flashcards
1
Q
Lesion Localization
A
- Symptoms and history can suggest a single locailzation along neuraxis ⇒ focal lesion (stroke or tumor)
- Damage to set of neuronal cell bodies ⇒ impair/eliminate behaviors controlled by those cell bodies.
- Axotomy of set of axons ⇒ impair/eliminate behaviors controlled by those neurons who’s axon ran through damaged axon bundle.
- Locazile lesion based on behavioral functions lost or altered.
-
Disease process may be widespread ⇒ multi-focal lesion (stroke or tumor) or diffuse disease
- Localize to neuronal type
- motor neuron disease
- mutliple discrete lesions
- multifocal conduction block
- metastases
- widespread areas
- infectious
- toxic
- metabolic processes
- Localize to neuronal type
2
Q
Anterograde Degeneration
CNS
A
aka Orthograde or Wallerian degeneration.
- Axonal degeneration of axon segment distal to axotomy
- Due to loss of trophic influence
- Consists of:
- fragmentation of the axon, terminal, and oligodendoglial myelin coat
- Oligodendroglia retract remaining processes
- debris removed by microglia and macrophages
3
Q
Transneuronal Degeneration
CNS
A
Target neurons, as well as axon segments distal to axotomy, both degenerate following axotomy.
Due to deprivation of axonal connection on the target cell.
4
Q
Retrograde Chromatolysis
CNS
A
Reaction of the cell body to axotomy.
Occurs during first 2-3 days .
-
Structural Changes
- Nissl bodies break up, shrink, and disperse
- Nucleus becomes eccentric
- Dendrites shrink
- Synaptic innervation to cell body and dendrites withdraw
-
Altered pattern of macromolecular synthesis
- Increase in RNA and protein production
- Will result in either recovery or apoptosis
- Inhibitors of protein synthesis can block axotomy-induced apoptotic cell death
- If recover initiated, cell’s metabolic machinery shifts to support regeneration
- structural proteins > transmitter-related products
- Process reaches max by 2-3 weeks post injury
- May appear normal in several months
5
Q
Axonal Regrowth
CNS
A
- Starts as multiple sprouts emamating from proximal stump of cut axon
- Do not grow more than a few micrometers
6
Q
Axotomy
Peripheral Nervous System
A
-
Wallerian degeneration
- Similar to process in CNS
-
Myelin coat degenerates
- Schwann cells
-
Nerve sheath remains intact
- perineurium, CT, etc
- Debris removed by microglia, macrophages, and surviving Schwann cells
-
Retrograde reaction
- Similar to process in CNS
- Nissl body dispersal
- Nuclear eccentricity
- Dendritic shrinkage
- Withdraw of synaptic innervation
-
Regrowth
- Multiple sprouts emamate from proximal stump
- If sprouts find remaining nerve sheath will grow back into sheath.
- Surviving Schwann cells multiply, repopulate nerve, and regenerate myelin sheath.
7
Q
Factors Affecting
Axotomy Response
A
-
Site of axotomy
- Cell more likely to die if injury closer to cell body
-
Age
- Embryonic & neonatal neurons more likely to show retrograde reactions and die after axotomy
- More dependent on trophic factors from synaptic targets
- Embryonic & neonatal neurons more likely to show retrograde reactions and die after axotomy
-
Sustaining Collaterals
- Axon collaterals likely protect parent cell body from retrograde reactions
- Total amount of axoplasm destroyed critical
- Trophic factors from synaptic target can be transported back via uninterrupted collaterals
- Axon collaterals likely protect parent cell body from retrograde reactions
8
Q
Axon Compression
A
- Due to tumor, ventricular swelling, or hemorrhagic mass
- Can elicit similar reponse at cell body as axotomy
- Recovery depends on extent of damage
9
Q
Deafferentation
vs
Denervation
A
Deafferentation ⇒ removal of electrical/physical neural input (afferents) to another neuron.
- If significant neural input removed, synaptic target neuron will:
- decrease dentritic size and complexity
- cell body shrinks
- show reduced metabolic output
- Intensity of reaction varies within different regions of the brain
- Similar atrophic response can occur by blocking neural activity without actual axonal injury
- Demonstrates importance of sensory information in brain development
Denervation ⇒ remvoal of neural electrical or physical inpur to a non-neural structure (e.g. muscle or organ).
- Targets will become atrophic if neural innervation lost
10
Q
Peripheral Regeneration
A
Severed axons outside of the dura mater are capable of complete axonal regeneration.
- May regrow injured axons and make appropriate synaptic contacts with targets.
- Appearance of multiple sprouts from cut end.
- Successful sprouts grow through neurolemmal sheath.
- Process at rate of 1-4 mm/day
- Reconnects with target.
- Not all axons regenerate completely or appropriately
- May grow back to wrong target
- poor motor control
- peculiar/painful sensations
- May form neuromas
- generate extreme intractable pain
- composed mainly of C-fibers
- associated with phantom limb syndrome
- May grow back to wrong target
- Electrical stimulation of injured nerve can accelerate regeneration & promote proper targeting
11
Q
Regeneration Failure
CNS
A
Cut axons within dura mater will sprout small branches but none will grow more than a few microns.
Possible causes:
-
Scarring
- Glial cells multiply and invade injured areas ⇒ gliosis
- Astrocytes, microglia, and invading blood cells clean up by phagocytosis
- Process forms a glial scar which blocks regeneration
-
Inhibition
-
Axonal outgrowth inhibited by secreted or displayed molecules within CNS
-
Oligodendroglia
- myeline-associated protein (MAG)
- Nogo
- Oligodendrocyte-myelin glycoprotein (OMgp)
-
Astroytes
- Chondroitin sulfate proteoglycans
- Meningeal cells
-
Oligodendroglia
- Role unclear as knock-out mice without improved regeneration
-
Axonal outgrowth inhibited by secreted or displayed molecules within CNS
-
Inflammation
- Immune cells invade in response to tissue damage
- Produce cytotoxic ROS and RNS
- Substances toxic to neurons and inhibits regeneration
-
Lack of guidance
- Wallerian degeneration in CNS triggers oligodendroglia to withdraw processes
- No structures remains to guide regrowth
- Reactive glia fill in prior site of myelin/axons causing scarring ⇒ sclerotic axons
12
Q
Collateral Sprouting
CNS & PNS
A
-
Normal axons that innervate postsynaptic sites close to degenerated axon terminals can develop sprouts
- supports some local regrowth
- may result in spontaneous functional recovery
- plasticity also occurs within normal CNS/PNSto adapt to changes
-
Following incomplete sponal cord injuries
- spared descending tracts and propriospinal axons can sprout
- compensates for injured tracts
- Sprouting may result in maladaptive plasticity
- allodynia
- hyperalgesia
- prevent re-establisment of approrpiate connects
13
Q
Calcium
A
- Intracellular [Ca2+] tightly regulated through active pumping and sequstration
- Elevated intracellular [Ca2+] activates degradative enzymes
- proteases
- endonucleases
- Degrades cytoskeleton, membrane lipids and proteins, DNA
- Mitochondrial calcium overload can trigger apoptosis.
- Can result in neuroal degradation.
14
Q
Ischemia
(anoxia)
A
2-5 minutes of oxgyen deprivation typically results in irreversible neuronal cell death.
- Extreme hypothermia can extend this period
- Without oxygen, mitochondrial ETC stops
- High metabolic demand of brain depletes ATP in 2-4 minutes
- Results in paired ion pumps
- influx of sodium
- activates Na/Ca-exchanger contributing to calcium overload in neuron
- Accumulation of lactic acid and free fatty acids ⇒ intracellular acidosis
- H+ exchanged for sodium ⇒ leads to accumulation of Ca2+
15
Q
Excitotoxicity
A
Occurs when excitatory neurotransmitters accumulate to abnormally high concentrations in extracellular space.
- Causes:
- defects in reuptake
- blunt neuronal injury ⇒ hemorrhagic stroke
- neuropathological conditions ⇒ epilepsy
-
Glumate is the main contributor
- normally quickly removed by excitatory amino acid transporters (EAATs)
- excess glutamate ⇒ abnormal influx of calcium
- opens sodium and cloride ion channels
- activates Na/Ca exchangers
- increases generation of ROS ⇒ oxidative stress
- influx of water ⇒ swelling and lysis
