Degeneration/Regeneration : Recovery of Function Flashcards
Degeneration in the PNS
1) Axon is cut
2) Proximal and distal ends seal off leaking axoplasm and swell
3) Rapid degeneration of axon and myelin sheath in zone of injury
4) BV damage
5) Macroglia & microglia absorb and destroy debris
6) Glial cells proliferate and form scar tissue
Orthograde degeneration
- away from cell body
- Begins immediately
- Glial cells push old axon away from post-synaptic target
- Entire distal axon degenerates
(distal or proximal depends on whether the neuron is sensory or motor)
Retrograde degeneration
- toward cell body
- lesion is close to cell body, the whole neuron may die
Transneural Degeneration
- secondary neuronal death
- dependent on the number of neurons prior to/after the injured neuron
Orthograde transneural degeneration
-1st order neuron lesioned with multiple 2nd order neurons needing to synapse with the lesioned 1st order neuron
Retrograde transneural degeneration
-2nd order neuron lesioned that had multiple 1st order neurons synapsing on it
Recovery of Function
- No single mechanism
- collective contribution of several mechanisms
- multiple intervention approaches
Early Mechanisms of Recovery
Resolution of…
- spinal shock
- edema
- Diaschisis
Spinal Shock
- transient suppression of all reflex and motor activity below level of lesion
- immediate effect of spinal damage
- Initial: paralyzed & anesthetized, Autonomics are suppressed; loss of circulatory tone, urine retention, and anhidrosis (absence of sweating)
Resolution of Spinal Shock
-Presence of spasticity means period of spinal is ending or has ended
Edema
- Local or remote
- compress cell body or axon > causing focal ischemia > disrupts neural function, synthesis and transportation of NT
- synapse become inactive and silent
Cytogenic edema
accumulation of intracellular fluid
Vasogenic edema
proteins and fluid leaking from damaged blood vessels
Resolution of Edema (Blood Clot resolution)
Corticosteroids
Osmotic diuretics
Hyperbaric O2
Ice pack cooling 48-72hrs
Diachisis
- Sudden functional depression of neural networks distant from the primary site can be due to a reduction in blood flow and/or metabolism
- 2nd order neurons are being inhibited
Resolution of Diachisis
-early recovery of function following stroke is due to the resolution of diaschisis
Redundancy of pathways
-Parallel pathways that may perform the same or similar functions may be unmasked
Ex) Damage to the Lateral CST; parallel motor pathways include the anterior CST, Rubrospinal tract, RST, VSTs
-Takes time for unmasking to occur
Later mechanisms of recovery
1) Collateral sprouting
2) Regeneration or regenerative synaptogenesis
3) Pre-synaptic compensatory response
4) Denervation Supersensitivity
Collateral Sprouting
- partial denervation to a target site occurs, the remaining neurons branch to occupy “old, damaged” sites and form synapses
- reinnervates denervated target
- Result = fiber-type grouping
- Leads to less control b/c one giant motor unit is controlling a muscle instead of two separate neurons
- It has been determined that not only axons sharing the same target send collateral sprouts to the vacated synapses, but sprouts may also arise from different brain regions. This may inhibit restitution of the original innervation pattern
Neural Regeneration
- Presynaptic axon is damaged
- Injured axon sprouts to new targets
Aberrant regenerative sprouting
- inappropriate targets are innervated
- axons innervate different muscle than they previously did, causing unwanted abnormal movements when the neurons fire
Pre-synaptic compensatory response
-More release of neurotransmitter per pre-synaptic membrane to compensate for damage
Ex) PD = symptoms only appear after 80% of dopamine producing cells have degenerated (substantia nigra)
Denervation Supersensitivity
-neurons lose input from another brain region
Ex) post-synaptic neurons in striatum become super-sensitive to dopamine (NT) in PD
True Regeneration
- Re-growth of axonal processes from a cut axon
- reform along the same pathway and form the same (or similar) synapses as prior to damage
- Travels short or long distance through or around scar tissue
- Form new synapses on correct target tissue, form new synapses on wrong target tissue, or die.
Growth cone
-Trying to find a target cell
-When growth cone arrives at target cell:
Synaptic vesicles form
Release of NT stimulates post-synaptic membrane to develop receptor sites
Failure to regenerate
- NOT due to the inability to sprout new growth cones!
- due to the environment the new axon grows in
PNS Regeneration
-Schwann cells line up to create a tunnel and guide axons to regenerate along same path and reconnect properly
CNS Regeneration
- Oligodendroglia do NOT line up to guide axons so they become entangled and/or scar tissue blocks CNS regeneration
- Astrocytes block or inhibit regeneration
Nogo
- produced by Oligodendrocytes
- inhibit axonal regeneration
Factors that enhance Regeneration
1) Pharmacological approaches
2) Remove scar tissue & suture nerve ends together
3) Nerve chambers
4) Placement of undifferentiated or embryonic tissue
Pharmacological approaches
NGF = nerve growth factor
- maintains normal growth of cell
- reduces scar tissue and enhances re-growth
Remove scar tissue & suture nerve ends together
- Difficult microscopic surgery
- Build “hair-thin bridges” across spinal gap
- White matter = lots of inhibitory factor
- Gray matter = easy to stimulate
- Connect white to gray and gray to white
Experiement: Spinal Cord repair in rats
- used fibrin and fibroblast growth factor as a natural adhesive
- @ 3 months, rat flex hind limbs
- @ one year, rats support weight BUT still not walking normally
- 10% axons crossing the gap = don’t have to re-grow whole spinal cord to obtain sig. function
Nerve chambers
- silicone tube implanted @ injury site and guides axons as they grow
- best recovery = 2.5x diameter of cut nerve and thin-walled tube
- small diameter axon = recovered greater
- tube with MP = 4x more regeneration than w/o MP
Placement of undifferentiated OR embryonic tissue
-guides regeneration across area of scarring
Endoderm
Mesoderm
Ectoderm
Stem Cells
- Progenitor (precursor) cells that can transform into wide variety of tissue
- Wrong cues = cancer
Ectoderm
Skin and nervous system
Mesoderm
Muscles
Endoderm
Internal Organs
Olfactory Tissue/Cells: Nasal Mucosa (OEC’s)
- promote regeneration
- myelin sheaths around growing and damaged axons
- secrete growth factors
- generating structural and matrix macromolecules that do axonal elongation
