Repair and Regeneration in the nervous system

Question 1

What are three types of nervous system repair?

Answer 1

1) regeneration of peripheral axons
2) repair of existing neurons in the CNS
3) replacement of injured or killed neurons

Question 2

What is the easiest type of neural damage to recover from?

Answer 2

peripheral axon damage

Question 3

What does the regeneration of peripheral axons require? (3 things)

Answer 3

development of axonal growth cone

guidance to the original target

synapse formation or reformation of the receptive field

Question 4

Peripheral axons include..

Answer 4

Includes axons from peripheral ganglia (e.g. autonomic nervous system) & axons from neurons in the CNS that project to the periphery (e.g. DRG sensory neurons or motor neurons in the ventral horn).

Question 5

What did Henry Head do?

Answer 5

Peripheral nerve regeneration experiment

Performed on himself(!!!); the external cutaneous nerve was transected and then re-appositioned (re-connected).

Question 6

When Henry Head’s arm started to heal, what order did he regain function?

Answer 6

The first axons to recover were those that mediated a coarse sense of touch and pressure (non-localized).

Later ability to detect light touch, thermal stimuli, pain, two-point discrimination and a degree of fine motor control.

Even at two years, full recovery had not occurred.

Question 7

What happens when a peripheral axon is damaged? How do the peripheral axons know where to grow? (general)

Answer 7

When the axon is cut, distal portion degenerates; although macrophages remove the damaged tissue & myelin, the Schwann cells are spared.

The proximal axon segment forms a growth cones and grows back towards the target using the distal stump (if present) and the Schwann cells as a guide towards the original target.

Question 8

What molecules in the extracellular matrix promote axon growth after peripheral nerve damage?

Answer 8

laminin and fibronectin

Question 9

How do the schwann cells promote peripheral axon growth?

Answer 9

Schwann cells also secrete molecules that promote regeneration, e.g. N-CAM & N-cadherin (cell adhesion molecules) & BDNF (nerve growth factor).

In fact Schwann cells are now used therapeutically to promote peripheral nerve regeneration.

Question 10

What are some molecular changes that happen in the regenerating axon to promote peripheral nerve regeneration?

Answer 10

Expression of receptors (e.g. Trk receptors) for the nerve growth factors in the growth cone. (respond to BDNF etc)

Reorganization of the axonal cytoskeleton to extend the axon + growth cone forward.

Increased or renewed expression of growth related genes in the nucleus normally associated with neural development; e.g. growth-associated protein 43 (GAP-43).

Question 11

What conditions promote quick and successful peripheral nerve regeneration?

Answer 11

In general, regeneration is more successful & occurs more quickly in conditions when the nerve is crushed as opposed to being cut because the pre-injury environment of the axon is preserved enough to promote growth and guide the axon to the correct target.

Axons are grouped into fasicles (bundles) that contained within membrane (perineurium). It is the extracellular in this fasicle that contains the growth-promoting molecules.

Question 12

What happens when a peripheral nerve is cut instead of crushed?

Answer 12

If the nerve is completely severed, the growth-promoting environment and guidance is lost.

Regeneration is still possible in these cases where the axon is cut, but it is slower compared to regeneration to a crush injury

Re-apposition of the cut ends can improve regeneration in this circumstance.

Question 13

What can improve peripheral nerve regeneration?

Answer 13

Activity can improve regeneration.

ex. diagram: Mouse leg nerve cut and then a nerve graft was placed to act as a bridge between the two cut ends.
The mouse that was given daily exercise showed improved regeneration over the control mouse.

Question 14

What about nerve grafts allows them to help with CNS damage?

Answer 14

Peripheral nerve sheaths and Schwann cells facilitate growth of damaged axons

Note that axons in the CNS cannot regenerate in this way (e.g. the spinal cord).

There is something about the peripheral nerve environment that is permissive for regeneration that is absent in the CNS.

However, it may be possible to use peripheral nerve tissue to promote axonal regeneration in the CNS.

In animals with optic nerve damage, a graft of the sciatic nerve allows the proximal axons to grow all the way to its central target (superior colliculus) and even form synapses (B).

Question 15

What components of the NMJ are preserved when the axon innervating it is cut?

Answer 15

schwann cells

Ach receptors on muscle fiber

Question 16

What mediates the capacity to reinnervate the NMJ?

Answer 16

Neurotrophins (NGF, BDNF) secreted at the NMJ that promote re-growing axon to recognize synaptic target and re-form the synapse (synaptogenensis)

Decrease in proteins that stabilize synapses (NT3, NT4) [these ensure that each muscle fiber is only innervated by 1 motor neuron]

Extracellular matrix molecules that help to identify the region of the muscle where the Ach receptors are located.

Activity from the muscles themselves.

Question 17

How does the CNS get damaged? (3)

Answer 17

1) Neuro-injury due to physical trauma to the brain or spinal cord (TBI = traumatic brain injury)
2) Hypoxia - lack of oxygen due to stroke, global O2 deprivation (e.g. drowning), and also neuro-injury above
3) Neurodegenerative diseases – Alzheimer’s, Parkinson’s, Huntington’s, ALS are examples

Question 18

When the CNS is damaged, what is typically the case?

Answer 18

Neurons in the CNS that undergo injury generally do not regenerate their conenctions to either entral or peripheral targets.

Question 19

What are the primary reasons for a lack of regeneration in the CNS?

Answer 19

1. Damage to the neurons in the CNS tend to elicit necrotic and apoptotic cell death and not just damage to axons & dendrites.
2. Cellular changes at site of injury tend to oppose axonal growth (opposite of changes in the periphery).

Question 20

Stimuli for inducing apoptosis (CNS)

Answer 20

• Glutamate excitotoxicity
• DNA damage
• Hypoxia
• Growth factor withdrawal (occurs through loss of synaptic connections that are the source of growth factors).
• Release of inflammatory cytokines

Question 21

Apoptosis is characterized by

Answer 21

chromosome condensation

DNA fragmentation

membrane blebbing

cytoskeletal changes

Question 22

How is B cl-2 related to apoptosis

Answer 22

glutamate and cytokinase stimulate the cell to block Bcl-2

when this is inhibited, it removes inhibition on the mitochondria.

then mitochondria release cytochrome C

then, that stimulates caspase, which signals apoptosis

Question 23

Review of what astrocytes, oligodendrocytes, and microglia do in the brain.

Answer 23

Astrocytes – general support for neurons (help maintain extracellular environment)

Oligodendrocytes – myelination of axons in the CNS

Microglia – host-defense in the brain; also remove (phagocytize) damaged tissue

Question 24

Why do glia survive nerve damage?

Answer 24

they’re more resistant to damage compared to neurons

injury also makes them actively oppose neuron repair and regeneration

Question 25

What are activated glia and what’s the role in CNS damage?

Answer 25

Proliferation of glial cells from quiescent glial precursors cells

Extensive growth of glial processes

Accumulation to the site of injury (microglia)

Release of signaling molecules , some of which promote apoptosis (cytokines)

Question 26

glial scar

Answer 26

cellular response to injury in the CNS

site is filled with activated glial cells

physical barrier and chemical barrier to growth and regeneration.

Question 27

invertebrate CNS repair

Answer 27

actually happens. axons grow towards each other to form their electric synapses

Question 28

What two factors need to occur in order for CNS neurons to be replaced?

Answer 28

CNS neurons can be lost to injury or disease. Can these neurons be replaced?

Need to account for

1. Growing new neurons – neurogenesis
2. Having those new neurons make appropriate connections in the adult brain

Question 29

Retinal growth in goldfish is an example of what?

Answer 29

adult neurogenesis in non-mammalian vertebrates.

As fish grow they need to expand the size of their retina (remember the retina is part of the CNS).

They do this by maintaining a population of retinal precursor cells that are capable of developing into the all the different cell types of the retina.

They also add cells to the optic tectum (region in the brain where the retinal ganglion cells project to).

Question 30

Neurogenesis in songbirds

Answer 30

Songbirds (e.g. zebrafinch) actively replace neurons in regions of the brain important for song production and perception.

These new neurons are derived from stem cells that resemble the radial glial cells in the developing mammalian brain.

These stem cells generate neuroblasts via asymmetric division and guide the resulting neural progenitors to the appropriate regions of the brain.

These new neurons are able to grow new connections (synapses) that allow them to correctly integrate themselves into the appropriate neural circuits.

Question 31

What two locations does adult neurogenesis in the mammalian brain occur?

Answer 31

olfactory bulb

hippocampus

Question 32

why is neurogenesis in adult mammalian brains controversial?

Answer 32

Controversial, partly because while it is possible to establish cell birthdates (e.g. w/ radioactive thymidine) it was impossible to distinguish if new cells were neurons or glia.

Question 33

Where are neural precursors located in areas of neurogenesis in the adult mammalian brain?

Answer 33

In both cases, the neural precursors are located in regions in regions of the brain referred to as subventricular zones (near the lateral ventricles). Site of proliferation.

Anterior subventricular zone (SVZ) for olfactory bulb neurons

Subgranular zone (SGZ) for hippocampus

Question 34

What is the fate of cells that are the product of neurogenesis in the adult mammalian brain?

Answer 34

Theses stem cells migrate to the appropriate region where they become local interneurons.

• Never seem to become projection neurons (neurons with long axons or dendrites that connect to other brain regions).
• Many newly-born neurons actually die

Question 35

Typical environment and factors involved in adult neurogenesis in mammals, specifically in the forebrain anterior subventricular zone (stem cell niche).

Answer 35

As in the developing brain, these adult neural precursor cells have features more like glial cells.

Also similar to the developing brain, cell-to-cell signaling appears to be important for proliferation and differentiation.

They always appear to be near blood vessels (source of signals that maintain or induce proliferation?)

As in other cases of neural or glial development, the stem cells must produce a transit amplifying cell.

This is a cell that can divide asymmetrically (& much faster) to neuroblast or glioblast.

They only have a limited number of divisions in them, so must be replaced by the reservoir of stem cells.

Question 36

How do cells get from the subgranular zone (SGZ) to the hippocampus?

Answer 36

Once the neuroblasts are produced they migrate to the hippocampus or olfactory bulb.

The distance between the SGZ and the hippocampus is relatively short and the cells migrate unassisted.

Question 37

How do neuroblasts travel from the SVZ to the olfactory bulb?

Answer 37

Neuroblasts traveling from the SVZ to the olfactory bulb have a long way to go. These cells travel a distinct path called the Rostral Migratory Stream (RMS)

This is essentially a conduit formed by multiple elongated glial cells.

The neuroblasts travel within this glial channel.

Question 38

Rostral Migratory Stream (RMS)

Answer 38

pysical path with conduit glial cells forming a tube that the neuroblasts can travel to the olfactory bulb in.

Question 39

What is functional reorganization?

Answer 39

It is possible to have functional recovery from neuro-injury or stroke without regenerating central axons or neurogenesis

This is accomplished by undamaged parts of the CNS forming new connections in such a way that restores motor behavior or sensory perception.

In the example here, a stroke patient has motor output to the hand lesioned at the pontine level.

There were areas of decreased cortical activity that are presumably linked to the damaged regions (indicated in red); primary and supplementary motor cortex

But there are also regions of increased cortical activity (green) that correspond in time with functional recovery of the hand.

Presumably what has happened is that following the loss primary motor cortex inputs to the hand lower motor neurons, other cortical regions (presumably already having some motor function) formed new connections with the hand’s spinal circuitry.

For this to happen there is growth of new synaptic connections, something that is supported in the adult brain.