Neural Regeneration

Question 1

What happens when peripheral nerve axons are injured?

Answer 1

The proximal part is able to regenerate distally (often only partially), regardless of whether the cell body is in a peripheral ganglion or the CNS

Question 2

What happens when central axons or neurons are damaged?

Answer 2

Some neurons die, some retract their processes but others are able to “sprout” and make new local connections in an attempt to compensate; regeneration is limited or non-existent

Question 3

Give a timeline of structural changes in PNS injury and regeneration

Answer 3

Before injury: central nucleus, dense Nissl substance
Up to 2 weeks post-injury: peripheral nucleus, chromolysis, Wallerian degeneration (rapid degeneration of distal axon and myelin sheath and phagocytosis by macrophages), muscle fibre atrophy
3 weeks post-injury: Schwann cell proliferation (forms compact cord), penetration of cell cord by growing axons (0.5-3mm growth/day)
3 months post-injury: restoration of electrical activity, muscle fibre regeneration

Question 4

What happens if neural regeneration in the PNS is unsuccessful?

Answer 4

The growing axon forms a bundle of fibres called a neuroma, which can be painful or cause unwanted sensation

Question 5

Why is neural regeneration more effective in crushed vs. cut peripheral nerves?

Answer 5

Because the Schwann cells and ECM in the distal segments of a crushed nerve provide a continuous guide for the growing axon

Question 6

What is the main therapeutic approach used to treat PNS injury?

Answer 6

Microsurgery, where proximal and distal stumps are reattached or a nerve graft is inserted

Question 7

What treatments for CNS neural injury are used to reduce the extent of the damage caused by the primary injury?

Answer 7

Tissue plasminogen activator (TPA) to dissolve the blood clot in stroke, decompression for SCI (e.g. removing vertebra if crushing the cord)

Question 8

What processes contribute to the secondary injury occurring within minutes to hours in SCI?

Answer 8

Ischaemia
Ca2+ influx
Lipid peroxidation and free radical production
Glutamate excitotoxicity
BBB breakdown

Question 9

What processes contribute to the secondary injury occurring within hours to days/weeks in SCI?

Answer 9

Immune cell infiltration/microglial activation

Influx of cytokines, chemokines, metalloproteinases

Question 10

What processes contribute to the secondary injury occurring within days/weeks in SCI?

Answer 10

Axonal degeneration
Demyelination
Apoptosis (neuronal and oligodendroglial)
Astrocytic gliosis and glial scar
Syrinx (fluid-filled cavity or cyst) formation, meningeal fibroblast migration

Question 11

What are 4 requirements for effective CNS repair and what does each involve?

Answer 11

Neuroprotection: protecting surviving cells
Axonal regeneration and functional integration: regrowing and remyelinating surviving neurons
Astrocytic gliosis modulation: preventing wound repair and scar formation from blocking axonal regeneration
Neural stem cells: replacing lost cells (either by mobilising endogenous cells or transplanting exogenous cells)

Question 12

How can a lack of trophic support for axonal regeneration be overcome?

Answer 12

Neurotrophins (e.g. NGF, BDNF) can be provided

Question 13

Give an example of an adverse effect of neurotrophin administration in SCI

Answer 13

Neuropathic pain

Question 14

List 6 processes that occur in astrocytic gliosis.

Answer 14

Upregulation of astrocyte cytoskeletal proteins (e.g. GFAP)
Astrocyte hypertrophy and proliferation
Development of interdigitate processes
Secretion of cytokines and GFs
Secretion of ECM (e.g. chondroitin sulphate proteoglycans, CSPGs)
Upregulation of expression of developmental axon guidance molecules

Question 15

What processes occurring in astrocytic gliosis aid axonal regeneration?

Answer 15

Wound sealing
BBB repair
GFs
Increased glutamate transporters

Question 16

What processes occurring in astrocytic gliosis hinder axonal regeneration?

Answer 16

Physical barrier
Molecular barrier
ECM deposition (CSPG, collagen IV)
Cytokines (including TNF-a, IL-1)

Question 17

What effect does astrocyte ablation have on axonal regeneration?

Answer 17

Outcome is worse than no inhibition; there is increased tissue destruction and degeneration, increased inflammation, and inhibition of BBB repair

Question 18

What effect do myelin debris and axon guidance molecules have on axonal growth?

Answer 18

Myelin inhibitors on myelin debris and axon guidance molecules on activated astrocytes bind to receptors on regrowing axons/dendrites and have an inhibitory effect

Question 19

Give some examples of myelin inhibitor molecules. What receptor do they bind to? What effect does this have?

Answer 19

Nogo, MAG (myelin-associated glycoprotein) and OMgp (oligodendrocyte/myelin glycoprotein) all bind to the Nogo receptor (NgR) on neurons to activate a Rho signalling pathway and inhibit axon growth

Question 20

What is the role of axon guidance molecules?

Answer 20

They are normally expressed during development and promote, repel or guide growing axons; however, many are upregulated or re-expressed after injury in adulthood

Question 21

Give 4 examples of axon guidance molecules

Answer 21

Semaphorins
Tenascin
Cell adhesion molecules (e.g. N-CAM, L1, N-Cadherin)
Eph/ephrins (e.g. EphA4, ephrinA5)

Question 22

Identify 2 effects rho kinase has on neurons

Answer 22

When the growth cone of a neuron contacts rho kinase, it retracts
Activates astrocytes

Question 23

List 7 characteristics of the PNS that are conducive to regrowth after injury

Answer 23

Simple structure
Quick degeneration of distal axon and myelin
Myelinating cell (Schwann cell) supports regrowth
Nerve structure often remains intact and provides a conduit for growth
Macrophages phagocytose debris
Schwann cells and macrophages only cell types present
Neurons survive (cell body intact)

Question 24

List 7 characteristics of the CNS that are inhibitive to regrowth after injury

Answer 24

Complex structure
Slow degeneration of distal axon and myelin
Myelinating cell (oligodendrocyte) inhibits regrowth
Neural structure often destroyed
Macrophages phagocytose debris and also enhance or diminish inflammatory response
Complex cellular environment (neuronal cell bodies, reactive astrocytes, oligodendrocytes, macrophages, other inflammatory cells)
Neurons often die (necrosis and apoptosis at the primary injury site)

Question 25

What are the 2 main neurogenic regions in the adult mammalian brain?

Answer 25

Subventricular zone (SVZ) of the lateral ventricle
Subgranular zone (SGZ) of the dentate gyrus in the hippocampus

Question 26

What is the difference between neurons in the SVZ and SGZ in terms of their response to injury?

Answer 26

Neurons in the SGZ can proliferate in response to injury within the hippocampus; neurons in the SVZ can migrate to the site of an injury and proliferate there

Question 27

What kind of stem cells can be used to replace lost neurons in the CNS?

Answer 27

iPSCs, ESCs (transplanted first or differentiated before being transplanted)
Other stem cell types including bone marrow, haematopoietic, mesenchymal (don’t become neurons but can secrete beneficial factors)