Neuronal Degeneration and Regeneration Flashcards Preview

IMS: Neuroanatomy > Neuronal Degeneration and Regeneration > Flashcards

Flashcards in Neuronal Degeneration and Regeneration Deck (19)
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1
Q

Lesion Localization

A
  • Symptoms and history can suggest a single locailzation along neuraxisfocal 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 widespreadmulti-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
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
    1. Nissl bodies break up, shrink, and disperse
    2. Nucleus becomes eccentric
    3. Dendrites shrink
    4. 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
  1. 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
  2. Retrograde reaction
    • Similar to process in CNS
    • Nissl body dispersal
    • Nuclear eccentricity
    • Dendritic shrinkage
    • Withdraw of synaptic innervation
  3. 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
  1. Site of axotomy
    • Cell more likely to die if injury closer to cell body
  2. Age
    • Embryonic & neonatal neurons more likely to show retrograde reactions and die after axotomy
      • More dependent on trophic factors from synaptic targets
  3. 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
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
  • 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
    • Role unclear as knock-out mice without improved regeneration
  • 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
16
Q

Riluzole

A

Used in the treatment of ALS

Blocks sodium channels.

Inhibits calcium influx and decreases excitotoxicity.

17
Q

Oxidative Stress

A
  • Neurons with high rate of free-radial production
    • Normally removed quickly by anti-oxidant enzymes
  • Accumulation of free radicals leads to:
    • proxidation and destruction of lipid molecules and DNA
    • disruption of calcium homeostasis
  • Cytotoxic immune cells responding to tissue damage can contribute to ROSs
18
Q

Aggregation

A

Neurodegenerative disorders characterized by proteinaceous accumulation within cell body or proximal axon.

  • Alzheimer’s disease
    • extracellular accumulation of amyloid
    • intracellular aggregates of tau
  • Parkinson’salpha-synuclein filamentous aggregates
  • Huntington’shuntingtin aggregates
  • ALS ⇒ neurofilament aggregates called Lewy bodies in proximal axons of motor neurons
19
Q

Apoptosis

vs

Necrosis

A

Methabolic pathways involved in neuronal degeneration can trigger either process.

  • Necrosis
    • Acute process with abrupt fragmentation of plasma membrane and vacuole formation within cell body.
    • Nucleus remains light and disintegrates.
    • DNA transcription and protein synthesis ceases.
  • Apoptosis
    • Preprogrammed cell death requiring both DNA transcription and protein synthesis.
    • Signaled via “death receptors” or mitochondrial release of cytochrome C.
    • Caused by oxidative stress, elevated calcium, extracellular signals
    • Detected through TUNEL staining of free 3’ OH ends