Lecture 16: Repair and regeneration

Functional Reorganization

After a stroke or neural injury, patients often recover due to reorganization of intact circuits

Does not reflect the regrowth or replacement or damaged neurons

Regrowth of Axons

→Requires reactivation of the process for axon growth and synapse formation

Seen primarily when sensory and motor nerves are damaged in the periphery

→ Leaves nerve cell bodies intact

Central nerve cell restoration

→ Sprouting → new dendrites, axons, and synapses must grow from an existing cell body

Generally fails, except over limited distances

→ Because of local overgrowth of glial cells and the production of signals that inhibit growth

Genesis of Neurons

Occurs rarely in adults → Peripheral olfactory receptor neurons

→ Nervous tissue must keep stem cells

→ Stem cells must be present in a region that keeps an appropriate environment for genesis and differentiation

→ Regeneration must keep the ability to repeat the migration and synapse formation during growth in order to regrowth local and long-distance connections

Peripheral nerve regeneration

A type of axon regrowth that results in a gradual, but usually incomplete restoration of sensory and motor function

Can be facilitated by surgical reapposition of the 2 ends of the severed nerve

Regeneration is more efficient after crushing vs cutting a nerve

Henry’s Head

A peripheral nerve regeneration experiment that monitored the return of sensation

Gradual return of sensitivity to pressure & touch that was not well localized starting ~6 weeks into recovery

→ Light touch, temperature discrimination, two-point discrimination recovered more slowly and less restoration

Schwann Cells

The glial cells that myelinate peripheral axons

Macrophages

The immune system cells that clear the degenerating remains of severed axons

Severed Peripheral Axon

• Axon segment distal to the cut degenerates

• Debris left by the dead axon is cleared by macrophages

• Proximal axon stump transforms into a growth cone

• Schwann cells proliferate & secrete growth-promoting signaling molecules

Peripheral Nerve graft

A treatment that can be used to treat a severed axon in the optic nerve

Offers the Schwann cell and connective tissue components that support Peripheral nerve regeneration

→ Central axons grow through the peripheral nerve graft

Limited effects → low # of synapses and functional capacity to restore vision

Peripheral nerve regeneration steps

• Extension of axons is the first step in peripheral nerve regeneration

• Next essential event: reinnervation of appropriate target tissues and reestablishment of synaptic connections

→Fair degree of imprecision in the reinnervation of specific targets

• Subsequent regeneration can (or cannot) be fairly faithful to the original pattern

CNS damage

1. Physical trauma (blunt force to the head)

2. Hypoxia (lack of oxygen, Ex: stroke)

3. Neurodegenerative diseases (Alzheimers, Parkinson’s, ALS)

Limited Regeneration CNS

1. Damage to brain tissue engages the mechanisms that lead to necrotic and apoptotic cell death for nearby neurons whose processes have been severed

2. A combination of glial growth and proliferation and microglial activity (immune functions that lead to local inflammation) actively inhibits growth

3. Upregulation of growth-inhibiting molecules

Glial Scarring

Caused due to extensive growth of processes from glial cells around the site of the injury

→ Local overgrowth & sustained concentrations of astrocytes & oligodendrocytes

Neurogenesis Regions

The olfactory bulb & the hippocampus

→ These are primarily GABAergic interneurons

Neurogenesis Components

• A low level of glial cell proliferation does continue throughout life

→ Astrocytes & oligodendrocytes

• Neural stem cells are often found in close proximity to blood vessels

→ Suggests they may be regulated by circulating as well as local signaling molecules

• Neuron replacement is gradual

• The limited capacity to replace neurons in an adult brain has offered some promise that, under the right conditions, neuron replacement might be used to repair the injured brain

• The CNS likely puts a premium on the stability of connections to ensure that learned behaviors are maintained

Nuclear Weapons and Neurogenesis

Fluctuations in environmental exposure to radioisotopes from nuclear weapons testing

Different levels of 14C in the brain due to weapons testing