Neural Regeneration

Question 1

What is the regenerative response to peripheral neural injury?

Answer 1

[cell body can be in a peripheral ganglion like a DRG or in CNS but nerve is peripheral] the proximal portion can regenerate distally

Question 2

What is the regenerative response to central neural injury?

Answer 2

do not regenerate well; neurons can die and/or retract processes (but sprout to make new local connections), glial scarring usually inhibits regrowth

Question 3

What are the general differences between the CNS and PNS that allows PNS regeneration?

Answer 3

general structure; cell types involved; molecular guidance/repellant cues that can inhibit growth of CNS axons

Question 4

What is the layered structure of peripheral nerves?

Answer 4

SC > dorsal and ventral roots > DRG and VRG > epineurium (around bundles of perineurium) > perineurium (around bundles of endoneurium) > endoneurium (around neurons) > sensory and motor neurons > nerve axons covered in Schwann cells and myelin –> skin and muscle

Question 5

Normal neuron cell bodies have

Answer 5

central nuclei and dense Nissl substance

Question 6

What is Nissl substance?

Answer 6

ribosomes which are actively transcribing RNA

Question 7

Damaged neuron cell bodies show

Answer 7

peripheral nuclei and loss of Nissl substance (chromolysis/chromatolysis)

Question 8

Up to 2 weeks post injury, peripheral nerves show

Answer 8

peripheral nuclei w/loss of Nissl substance in cell bodies; Wallerian degeneration - degeneration of axon and myelin sheath below site of injury, debris is phagocytosed by macrophages; muscle atrophy

Question 9

Regeneration of peripheral nerves occurs how soon after injury?

Answer 9

~3weeks

Question 10

3 weeks post-injury, peripheral nerves display?

Answer 10

nuclei more central; proliferation of Schwann cells forming a compact cord; axon sprouting - hopefully enters Schwann cell cord and grows

Question 11

About 3 months post-injury, peripheral nerves display

Answer 11

regeneration may be successful - restoration of electrical activity, reforming of synapses, myelin sheath (may be thinner), reversal of muscle atrophy

Question 12

A neuroma forms when

Answer 12

the axon misses the Schwann cell cord and does not connect to the peripheral nerve segment; this results in continued axon growth and sprouting facilitated by factors released from Schwann cells

Question 13

What is the impact of myelination by oligodendrocytes in the CNS (vs Schwann cells in the PNS) on regeneration?

Answer 13

Oligodendrocytes are inhibitory of regrowth; Schwann cells are supportive for regrowth

Question 14

What processes lead to secondary injury in minutes-hours post-injury?

Answer 14

ischaemia: limited blood flow causing hypoxia; Ca2+ influx; lipid peroxidation and production of free radicals (toxic to cells); glutamate excitotoxicity (can’t be mopped up); BBB breakdown

Question 15

What processes lead to secondary injury in hours to days/weeks post-injury?

Answer 15

activation of immune cells migrated from periphery and of resident microglia releases inflammatory cytokines, chemokines, and metalloproteases

Question 16

What processes lead to secondary injury in days/weeks post-injury?

Answer 16

ongoing degeneration (inflammatory mediators); axonal degeneration an death; demyelination of remaining axons; oligodendrocyte death; myelin fragments (inhibitory; slowly phagocytosed); astrocytic gliosis and glial scarring inhibits growth; syrinx (cyst) formation; meningeal fibroblast migration

Question 17

How might neural regeneration be promoted?

Answer 17

neuroprotection (of surviving cells); axonal regeneration & functional integration (regrowth and remyelination); modulation of astrocytic gliosis (important in wound repair and scar formation but scar blocks regeneration); neural stem cell (endogenous activation or exogenous transplantation)

Question 18

What inhibits axonal regeneration?

Answer 18

lack of trophic support and inhibition by the injury environment

Question 19

What trophic support is needed in axonal regeneration?

Answer 19

growth promoting factors like neurotrophins (NGF, BDNF)

Question 20

NGF

Answer 20

nerve growth factor

Question 21

BDNF

Answer 21

brain-derived neurotrophic factor

Question 22

What factors of the injury environment inhibit axon regrowth?

Answer 22

astrocytic gliosis and glial scarring; myelin (and oligodendrocte) inhibitors; developmental guidance molecules presenting at the wrong spots

Question 23

What happens to astrocytes in astrocytic gliosis?

Answer 23

upregulation of astrocyte cytoskeletal proteins (GFAP - glial fibrillary acidic protein); hypertrophy and proliferation of cells; interdigitation of processes; secretion of cytokines and growth factors; secretion of ECM and proteoglycans; upregulation of expression of developmental axon guidance molecules

Question 24

What is the purpose of glial scar formation?

Answer 24

form a barrier between undamaged tissue and the injury site

Question 25

How can astrocytic gliosis be modulated to promote neural regeneration?

Answer 25

promote wound healing, BBB repair, secretion of growth factors (NGF, BDNF), increase glutamate transporters; reduce physical and molecular barriers, ECM deposition (CSPG, collagen IV) and cytokines (TNFa, IL-1)

Question 26

How do myelin inhibitors and axon guidance molecules inhibit axon growth?

Answer 26

axons that encounter myelin debris or guidance molecules (upregulated on astrocytes) will stop growing

Question 27

What are myelin inhibitors?

Answer 27

myelin proteins Nogo, myelin associated glycoprotein (MAG), and ogliodendrocyte/myelin glycoprotein (OMgp); all of which bind to Nogo receptor on neurons which signals via Rho to inhibit growth

Question 28

How can myelin inhibitors be blocked to promote axonal regeneration?

Answer 28

antibodies agains proteins eg Anti-Nogo antibody to prevent binding to the Nogo receptor; Rho inhibitors to inhibit Rho signalling that stops growth

Question 29

What axon guidance molecules are upregulated or re-expressed after injury?

Answer 29

semasphorins, tenascin, cell adhesion molecules (neural-CAM, L1, N-cadherin_, Eph/ephrins (EphA4, ephrinA5)

Question 30

Why is rho kinase a potential target?

Answer 30

it's common to the pathways of Ephrin, semaphorin, and CSPG (ECM) which inhibit regeneration; it is what tells the axon to stop growing (growth cone) when it encounters inhibitors in the environment; it also activates astrocytes

Question 31

How can activation or transplantation of neural stem/progenitor cells promote neural regeneration?

Answer 31

replace neurons or oligodendrocytes (for myelination)

Question 32

What areas of the brain contain neural stem cells that can make new neurons?

Answer 32

subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus in the hippocampus (memory/learning, anxiety)