Degeneration and Regeneration Recovery of Function Flashcards
Degeneration in the PNS
- Axon is cut (in this case, complete separation)
- Proximal and distal ends of axon seal off the leaking axoplasm and swell [close off fast]
- Rapid degeneration of axon and myelin sheath away from the zone of injury [towards axon]
- Blood vessel damage- can cause more swelling, which can cause more compression and further the injury
- Macroglia & microglia cells …
-PNS Degen.
-absorb and destroy debris
-Macroglia
Schwann cells (PNS)
Oligodendrocytes (CNS)
Astrocytes (CNS)
-Microglia (CNS)
- Glial cells…
proliferate and form glial scar tissue [can deflect the newly growing axons-so want to prevent them from growing too much scar tissue]
- Orthograde degeneration (Wallerian)….
-Degeneration “distal” to zone of injury (away from cell body*)
-Begins immediately
–Glial cells push old axon away from post-synaptic target
Entire distal axon degenerates (axon and myelin phagocytized)
- Retrograde degeneration
- Degeneration “proximal” to zone of injury (toward cell body*)
- Up to 1st axon collateral or only 1-2 nodes of Ranvier
- If site of lesion is close to the cell body -> the neuron may die
- If distal to cell body, neuron may live if it properly reconnects to the target tissue
Transneural Degeneration
secondary neuronal death of neurons more “proximal” or “distal” to/from the damaged neuron along the neural pathway
Amount of transneural degeneration is dependent on the number of neurons prior to or AFTER the injured neuron
Ex: if damaged neuron was one that had multiple axon branching or synapsed on multiple 2nd order neurons > result is widespread orthograde transneural degeneration
Amount of transneural degeneration is dependent on the number of neurons PRIOR TO or after the injured neuron
Ex: If damaged neuron was a 2nd order neuron that had multiple 1st order neurons synapsing on it > widespread retrograde transneural degeneration
Transneural Degeneration: Potential mechanisms
- Some type of trophic interaction between neurons to maintain the chain’s health
- Maybe that working electrochemical circuit is necessary to maintain chain’s health
Recovery of Function
- No single mechanism accounts for all of the recovery phenomenon following a lesion of a nerve.
- Recovery results from the collective contribution of several mechanisms toward a common goal of reorganization.
- This supports the idea of using as many of the intervention approaches as possible to tap into all of the recovery of function mechanisms.
Early Mechanisms of Recovery
Resolution of: spinal shock, edema or blood clot, diaschisis unmasking of redundant pathways
are probably mechanisms for early recovery of function
Spinal Shock
- transient suppression of all reflex and motor activity below the level of the lesion
- is an immediate effect of spinal damage
- initial stage
- -body below the level of the lesion is paralyzed & anesthetized
- -Autonomics are suppressed; loss of circulatory tone, urine retention, and anhidrosis (absence of sweating)
- later stages
- -some/any reflex activity returns in somatic and autonomic structures
Spinal Shock Duration
Duration:
-species dependent
- Subsequently - reflexes become exaggerated; hypertonicity
- Resolution of spinal shock > recovery
- –Presence of spasticity means period of spinal is ending or has ended.
Early Transient Events that Depress Brain Function: Edema
- Common response following brain injury
- Edema can be local or remote from the site of injury
- may compress neuron’s cell body or axon, causing focal ischemia, which disrupts neural function, including synthesis and transportation of neurotransmitter.
- Eventually the synapse become inactive and silent.
Cytogenic edema
accumulation of intracellular fluid
Vasogenic edema
proteins and fluid leaking from damaged blood vessels
Diaschisis
- “Diaschisis is a transient CNS disorder involving loss of function … because of loss of input from an anatomically connected injured area of the brain.”
- “The sudden functional depression of brain regions distant from the primary site can be due to a reduction in blood flow and/or metabolism.”
- “It has been proposed that early recovery of function following stroke is due to the resolution of diaschisis”
Diaschisis in the…
inhibition or the depression
of other neural networks.
Redundancy of ineffective synapses, silent synapses or latent pathways….
- Parallel pathways that may perform the same or similar functions may be unmasked
- Good example: Damage to the Lateral CST; parallel motor pathways include the anterior CST, Rubrospinal tract, RST, VSTs
- Takes time for the unmasking to occur
Multiple mechanisms underlying “LATER” Recovery of Function
- Collateral sprouting
- Regeneration or regenerative synaptogenesis
- Pre-synaptic compensatory response
- Denervation Supersensitivity
- Collateral sprouting (takes time)
- When partial denervation to a target site occurs, the remaining neurons branch to occupy “old, damaged” sites and form synapses. Results in fiber-type grouping.
- Axon of a remaining neuron forms a collateral sprout to reinnervate denervated target
- End Result: leads to less control b/c 1 giant motor unit is controlling a mm instead of 2 separate neurons
- Sprouting occurs in the PNS and CNS of higher vertebrates
- Neural Regeneration
- Recovery mechanism
- Presynaptic axon is damaged
- Injured axon sprouts to new targets
what may collateral sprouting inhibit?
may inhibit restitution of the original innervation pattern
- Pre-synaptic compensatory response
- More release of neurotransmitter per pre-synaptic membrane to compensate for damage
- Ex: PD- clinical symptoms only appear after approximately 80% of dopamine producing cells have degenerated (substantia nigra)
Aberrant regenerative sprouting in PNS
-Axon sprouting can cause problems when inappropriate targets are innervated.
-After injury, motor axons innervate different muscle than they previously did, causing unwanted abnormal movements
[Ex: Bell’s Palsy]
-Usually lasts no more than a few months
- Denervation Supersensitivity
- Occurs when neurons lose input from another brain region, e.g. postsynaptic neurons in the striatum become super-sensitive to dopamine in pt with PD
- “spread out” and make a larger target and are more sensitive to any neurotransmitter
Regeneration Definition
Re-growth of axonal processes which reform along the same pathway and form the same (or similar [functional]) synapses as prior to damage
Regenerative sprouts grow from…
- cut axon
- Sprouts may need to travel short or long distances through or around glial scar tissue
- Either form new synapses on appropriate target tissue, form new synapses on inappropriate target tissue, or die.
Regeneration mimics…
- Mimics Embryonic Neural Migration
- Forward end of neural process (axon or dendrite) forms a growth cone
When growth cone arrives at target cell
Synaptic vesicles form
Release of neurotransmitter stimulates postsynaptic membrane to develop receptor sites
Regeneration in PNS
-the PNS of mammals, humans, and lower vertebrates do regenerate
-Regenerated axon has an inter-nodal length, axon diameter and conduction velocity that is 80% of normal
1 mm/month [Noback]
1-3 mm/month [NIH]
Regeneration of PNS in humans
- Schwann cells provide pathways (tunnels) that guide axons to regenerate along same path and reconnect properly
- Form pathways across the scar tissue
- Multiple axonal sprouts are generated and the sprout that reaches the target tissue survives (mimics development)
Regeneration of CNS in humans
Oligodendroglia glial cells - apparently do not have the ability to line up as guiding tubes so that axons become entangled and/or scar tissue blocks CNS regeneration
Astrocytes – appear to block or inhibit regeneration
Regenerative sprouting
- Neural regeneration occurs most frequently in PNS bc Schwann cells produce nerve growth factor, which help recovery.
- Astrocytes and microglia form glial scars, which physically block axonal regeneration
- Oligodendrocytes produce Nogo (neurite outgrowth inhibitor) -> inhibits axonal regeneration
Pharmacological approaches to enhance regeneration
- NGF (nerve growth factor) - a high molecular weight protein that appears to be produced or taken up by nerve end feet and transported to the cell body
- Possibly plays a role in maintaining normal growth or health of the cell
- NGF appears to reduce scar tissue and enhance re-growth
Remove scar tissue & suture nerve ends together to enhance regeneration
- Difficult microscopic surgery
- Cut the spinal cord and widened the gap (removed 5 mm of spinal cord) in rats to ensure that no tissue remained to produce false-positive results
- High amount of inhibitory factor in white matter, but growth in gray matter relatively easy to stimulate
- Surgeons carefully connected white matter to gray and gray matter to white
Remove scar tissue & suture nerve ends together
- used fibrin and fibroblast growth factor as a natural adhesive
- nothing happened first 3 months
- ~3 months, rat started flexing the hind limbs
- at 1 year post, rats could support their weight, move their rear legs, BUT still not walking normally
- probably very few axons crossing the gap, no more than 10%; this means we don’t have to re-grow the whole spinal cord to obtain significant function
Nerve chambers that enhance regeneration
- silicone tube implanted at the injury site
- best recovery occurred when the tube was 2.5 x the diameter of the cut nerve
- best recovery when the tube was thin walled but not so thin that it collapsed
- adhesive matrix forms on the tube surface and guides the axons as they grow
Nerve chambers recovery
- small diameter axons (pain sensation & sweating) recovered to a greater degree than larger diameter MNs
- methylprednisolone (MP) AND guidance tubes -> contained 4x more regenerated axons than tubes without MP
Placement of undifferentiated or embryonic tissue enhance regeneration
- Placement of undifferentiated or embryonic tissue in the path of re-growth to assist the guiding and regeneration across the area of scarring
- Have had success in experimental animals
- may provide a bridge across the scar tissue, a path to target tissue, & chemically stimulate re-growth
Stem Cells
- precursor or progenitor cells that have the potential to transform into a wide variety of tissue
- As our CNS develops, embryonic stem cells evolve into more specialized adult neural stem cells.
- these adult cells can differentiate into neuron- or glial-restricted precursor cells
- -Neuron precursor cells-> neurons
- -Glial precursor cells -> oligodendrocytes & astrocytes.
- Given the wrong cues, stem cells can turn into physiological troublemakers -> cancer.
Embryonic Stem Cells
- after an egg is fertilized, an embryo is formed, which then splits into a two-cell embryo. This division goes on, successively creating 8, 16, 32, 64, 128-cell embryo
- 4-6 days, the cells rearrange into 2 layers:
- -Outer layer which will develop into placental and amniotic tissue
- -Inner layer or a few dozen cells called the inner-cell mass (ICM) which turns into everything else.
- -Now labeled a blastocyst, the embryo is about 0.1-mm across or the size of the period at the end of this sentence.
Blastocyst & Inner Cell Mass
- After about 2 weeks, the ICM cells start to organize into 3 specific layers that become our various tissues.
- -Ectoderm
- -Mesoderm
- -Endoderm
-As the cells continue to develop, they increasingly lose their omnipotent nature
Embryonic Stage (2-8 weeks): Ectoderm develops into…
Sensory organs
Epidermis
Nervous system
Embryonic Stage (2-8 weeks): Mesoderm develops into…
Dermis
Muscles
Skeleton
Excretory and circulatory systems
Embryonic Stage (2-8 weeks): Endoderm develops into…
Gut, liver, pancreas
Respiratory system
To obtain embryonic stem cells…
-ICM cells are isolated before they start turning into these layers, and are grown in culture
Cell Sources
- Embryonic Stem Cells – IVF Clinics
- Fetal Stem Cells
- Adult Stem Cells (Bone Marrow, Blood, etc.)
- Umbilical Stem Cells (umbilical cord blood, etc.)
Olfactory-Related Programs
- Carlos Lima (Portugal), olfactory tissue, OMA (olfactory mucosa autograft)
- Because olfactory tissue is exposed to the air we breathe, it contains cells with considerable turnover potential, including renewable neurons, progenitor stem cells, & olfactory ensheathing cells (OECs) NASAL MUCOSA
- When transplanted into the injured spinal cord, OECs potentially promote axonal regeneration by producing insulating myelin sheaths around both growing & damaged axons, secreting growth factors, & generating structural & matrix macromolecules that lay the tracks for axonal elongation
