Degeneration and Regeneration Recovery of Function Flashcards
1
Q
Degeneration in the PNS
A
- 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
2
Q
- Macroglia & microglia cells …
A
-PNS Degen.
-absorb and destroy debris
-Macroglia
Schwann cells (PNS)
Oligodendrocytes (CNS)
Astrocytes (CNS)
-Microglia (CNS)
3
Q
- Glial cells…
A
proliferate and form glial scar tissue [can deflect the newly growing axons-so want to prevent them from growing too much scar tissue]
4
Q
- Orthograde degeneration (Wallerian)….
A
-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)
5
Q
- Retrograde degeneration
A
- 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
6
Q
Transneural Degeneration
A
secondary neuronal death of neurons more “proximal” or “distal” to/from the damaged neuron along the neural pathway
7
Q
Amount of transneural degeneration is dependent on the number of neurons prior to or AFTER the injured neuron
A
Ex: if damaged neuron was one that had multiple axon branching or synapsed on multiple 2nd order neurons > result is widespread orthograde transneural degeneration
8
Q
Amount of transneural degeneration is dependent on the number of neurons PRIOR TO or after the injured neuron
A
Ex: If damaged neuron was a 2nd order neuron that had multiple 1st order neurons synapsing on it > widespread retrograde transneural degeneration
9
Q
Transneural Degeneration: Potential mechanisms
A
- 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
10
Q
Recovery of Function
A
- 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.
11
Q
Early Mechanisms of Recovery
A
Resolution of: spinal shock, edema or blood clot, diaschisis unmasking of redundant pathways
are probably mechanisms for early recovery of function
12
Q
Spinal Shock
A
- 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
13
Q
Spinal Shock Duration
A
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.
14
Q
Early Transient Events that Depress Brain Function: Edema
A
- 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.
15
Q
Cytogenic edema
A
accumulation of intracellular fluid
16
Q
Vasogenic edema
A
proteins and fluid leaking from damaged blood vessels
17
Q
Diaschisis
A
- “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”
18
Q
Diaschisis in the…
A
inhibition or the depression
of other neural networks.
19
Q
Redundancy of ineffective synapses, silent synapses or latent pathways….
A
- 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
20
Q
Multiple mechanisms underlying “LATER” Recovery of Function
A
- Collateral sprouting
- Regeneration or regenerative synaptogenesis
- Pre-synaptic compensatory response
- Denervation Supersensitivity
21
Q
- Collateral sprouting (takes time)
A
- 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
22
Q
- Neural Regeneration
A
- Recovery mechanism
- Presynaptic axon is damaged
- Injured axon sprouts to new targets
23
Q
what may collateral sprouting inhibit?
A
may inhibit restitution of the original innervation pattern
24
Q
- Pre-synaptic compensatory response
A
- 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)
25
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
26
4. 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
27
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
28
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.
29
Regeneration mimics...
- Mimics Embryonic Neural Migration
| - Forward end of neural process (axon or dendrite) forms a growth cone
30
When growth cone arrives at target cell
Synaptic vesicles form
Release of neurotransmitter stimulates postsynaptic membrane to develop receptor sites
31
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]
32
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)
33
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
34
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
35
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
36
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
37
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
38
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
39
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
40
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
41
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.
42
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.
43
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
44
Embryonic Stage (2-8 weeks): Ectoderm develops into...
Sensory organs
Epidermis
Nervous system
45
Embryonic Stage (2-8 weeks): Mesoderm develops into...
Dermis
Muscles
Skeleton
Excretory and circulatory systems
46
Embryonic Stage (2-8 weeks): Endoderm develops into...
Gut, liver, pancreas
| Respiratory system
47
To obtain embryonic stem cells...
-ICM cells are isolated before they start turning into these layers, and are grown in culture
48
Cell Sources
1. Embryonic Stem Cells – IVF Clinics
2. Fetal Stem Cells
3. Adult Stem Cells (Bone Marrow, Blood, etc.)
4. Umbilical Stem Cells (umbilical cord blood, etc.)
49
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
