Repair and Regeneration of Nervous System; Adult Neurogenesis

Stroke or injury patients do have the ability to regain function over time:

• Movement in paralyzed limbs can improve (especially with physical therapy)

• Speech impairments will diminish with speech therapy

Stroke recovery is not thought…

to reflect regrowth of replacement of damaged neurons

Undamaged brain regions become…

reorganized to support functions that were disrupted due to the injury

Explain Figure 26.2- Altered cortical activity patterns are correlated with functional recovery after a focal stroke

(A) Compilation of about 20 people that show where declines are occurring in the brain. Red= loss of activity and green= areas that increase activity to help compensate for this loss

(B) and (C) correspond to a specific patient, motor deficits in hand, shows that patient recovers that function over time. Increase in activity right after stroke.

3 types of neuronal repair that could occur

1. Regrowth of axons (peripheral)

2. Restoration of damaged central nerve cells (injured but survive)

3. Generation of New Neurons (replace those that have been lost)

3 Components of Regrowth of axons (peripheral ganglia or peripherally projecting axons)

1. Requires reactivation of the developmental processes for axon growth and guidance and initial synapse formation

2. Seen primarily when sensory or motor nerves are damaged in the periphery; nerve cell bodies are intact

3. Peripheral nerve regeneration is the most easily accomplished type of repair in the nervous system and the most clinically successful

Explain Figure 26.3- Regrowth of Axons

• Shows neuron injury, gets damaged, then goes back to being repaired

• Recovery seen in periphery but not in CNS

Restoration of damaged central nerve cells (injured but survive)

• Requires that nerve cells are capable of restoring their damaged processes and connections to some level of functional integrity

• Several developmental mechanisms must be re-engaged

  • Appropriate regulation of polarity in order to distinguish axon and dendrites

  • Trophic signaling

• Regrowth of neuronal and glial elements in a more complex
  environment

• Local overgrowth of glial cells and production of signals that inhibit neuron growth

• Inflammatory molecules may suppress reactivation of cellular mechanisms for axonal and dendritic growth

Figure 25.3- Restoration of damaged CNS Cells

• CNS cells get damaged but unlike PNS cells, they do not get repaired and are instead lost, because not able to get trophic support they need, unable to remake connections.

• Could occur but does not

Generation of New Neurons (replace those that have
been lost)

• Adult neuronal genesis occurs rarely

• For such repair to occur the following must be met:

  • Retention of a population of neural stem cells able to give
    rise to all cell types in the brain region that has been
    damaged

  • Neural stem cells must be present in a “niche” that provides
    the appropriate environment for genesis and differentiation of
    new neurons and glia

  • Regenerating tissue must retain the capacity to recapitulate
    migration, outgrowth of processes, and synapse formation to
    form local and distant functional networks
    

Explain this image

• If stem cells are there, they can proliferate and differentiate to join network and replace damaged cells

• Not done in CNS

• This in theory could occur but in actuality does not

Head’s experiment 1905 - Peripheral nerve regeneration

• Early 1900’s – it was clear that damage to a peripheral nerve resulted in a gradual but incomplete restoration of sensory and motor function; the speed and precision of
  recovery could be facilitated by surgically connecting the two ends

• British neurologist Henry Head decided to perform a nerve transection on himself; this was documented in a paper published in 1905.

• First indication of recovery was the return of general sensitivity to pressure and touch

• Sensitivity to light touch, temperature discrimination, pinprick, two-point discrimination, and fine motor control
  were slower to recover and did not fully recover after 2
  years

Figure 26.4 Henry Head’s peripheral nerve regeneration experiment

• Cut nerve and then joined them back together

• Areas of deficit, hand and thumb regained sensation, less or more simulation response

2 Major elements that contribute to peripheral axon regrowth and reinnervation of target

1. Schwann Cells

2. Macrophages

   • These two only present in peripherary and not CNS

Schwann cells

glial cells that myelinate peripheral
axons

Macrophages

immune cells that clear the degenerating remains of of severed axons

In addition, these schwann cells and macrophages secrete molecules that are…

essential for successful regeneration; mimic the
environment that supports axon guidance and
growth during early development

Regeneration is more efficient after…

crushing vs. cutting a nerve

Figure 26.6- Molecular and Cellular Response that promote peripheral Nerve Regeneration

• Shows injury to peripheral nerve

• After damage occurs, damaged parts of axon need to be removed and macrophages remove debris

• Increase transcription for genes that are related to growth of the axons

Peripheral nerve graft of schwann cell, basal lamina (extracellular matrix), and connective tissue will promote growth of…
Why doesn’t this happen normally in the CNS?

CNS axons

Reestablishment of synaptic connections is necessary
for successful recovery of function

Most thoroughly characterized at the neuromuscular junction.

Figure 26.8 Reinnervation of muscles following peripheral motor nerve damage

From experiment that shows motor neurons that innervate muscle fibers, if nerve is cut, it gets degenerated, but overtime the axons can regrown and find target muscle fibers, and synapse needs to be reestablished to regain function

• Axon= green

• Red= Ach receptors (on muscle fibers itself for junction)

25 days later, reestablished back to normal- in periphery

not seen in CNS

Very little axon growth and reestablishment of functional
connections within the…

central nervous system following injury

3 ways damage occurs in the CNS

1. external physical trauma

2. hypoxia – lack of oxygen often created by lack of blood flow (ischemia) due to stroke

3. neurodegenerative diseases

   • All result in some amount of neuronal death either immediately or over time

CTE

• Deposits of Tau protein that accumulate that indicate brain damage

• overwhelm the ability of the

  skull and the fluid-filled cushion created

  by the subarachnoid space to protect the

  brain from shearing forces. These forces

  can cause acute bleeding around the

  meninges or within brain tissue.

• One of the most striking differences in the consequences of central versus peripheral nerve cell damage is the extent of cell death that occurs after direct damage to the brain.

• Neuronal cell death in the CNS is seen regardless of the type of damage (traumatic, hypoxic, or degenerative).

Factors that lead to limited regeneration in the CNS

1. Damage to brain tissue tends to engage mechanisms that lead to necrotic and apoptotic cell death of nearby neurons

2. Cellular changes at the site of injury do not recapitulate developmental signaling that supports growth

   • Glial growth and proliferation and microglial activity actively inhibit growth

3. Upregulation of growth inhibiting molecules

   • Neuronal cell death in the CNS is seen regardless of the type of damage; studied most extensively in brains where hypoxia has occurred due to local vascular occlusion (stroke)

Figure 26.9 Consequences of hypoxia/ischemia in the mammalian brain

• White= cells that have died

• Yellow= stain for apoptotic protein

• Glutamate is released alot when ther is cns injury, stimulates apoptosis pathways

• Bd2 promotes capsapse to promote apoptosis

Some stimuli for apoptosis

• DNA damage

• Hypoxia

• Stress

• Growth Factor Withdrawal

Apoptosis

• Chromosome condensation

• DNA fragmentation

• Membrane blebbing

• cytoskeletal changes

Figure 26.10 The reaction of the three major classes of glia in the CNS to local tissue damage

• Injured vs uninjured

• Glial cells, astrocytes, microglia overproduced at injury site to get int he way, which prevents axons to find target because of glial scarring, can also affect axons that are near

• Growth inhibitng

• Local proliferation of otherwise quiescent
  glial precursors and extensive growth of
  processes from existing glial cells around the injury site -- -lead to glial scarring

• Depending on the type of injury and the time elapsed following injury, local glial either alter the relationships among remaining neurons, or they become the dominant cell type and replace lost neurons and degenerated processes ---- long term glial scar

Figure 26.11 Cellular response to injury in the CNS

• In CNS, has oligodendrocytes

• Microglia can be there to sort of act as macrophages, but inactuality do not really clear away. debris

• Microglia and Asrtocytes release signlas that inhibit growth of axon, glial scar occurs, nothing left to promote growth, and neuron ends up dying

Fig 26.14- Neurogenesis regions in mammalian brain

1. Subventicular Zone

2. Dentate Gyrus of hippocampus

3 Factors that impact neurogenesis in the Dentate Gyrus

1. Exercise and anti-depressants increase cell proliferation in the DG

2. Stress decreases cell proliferation in the DG

3. Drugs of abuse, including opiates, decrease cell proliferation in the DG