These various observations on adult plasticity indicate that normal experience can alter the strength of existing synapses and might even elicit some local remodeling of synapses and circuits. More extensive growth and remodeling are stimulated by nervous system injury.

Traumatic injury, interruption of blood supply, and degenerative diseases all can damage axons in peripheral nerves, or neuronal cell bodies and synapses in the more complex circuitry of the brain or spinal cord. When peripheral nerves are injured, the damaged axons regenerate vigorously and can regrow over distances of many centimeters or more. Under favorable circumstances, these regenerated axons can also reestablish synaptic connections with their targets in the periphery. In contrast, CNS axons typically fail to regenerate (Figure 25.16). As a result, axonal damage in the retina, spinal cord, or the rest of the brain leads to permanent blindness, paralysis, and other disabilities. What explains this difference in the regeneration of peripheral nerves compared to axonal regeneration in the brain or spinal cord?

Figure 25.16

Different responses to injury in the peripheral (A) and central (B) nervous systems. Damage to a peripheral nerve leads to series of cellular responses, collectively called Wallerian degeneration (after Augustus Waller, the nineteenth century English (more...)

Successful regeneration in peripheral nerves depends on two critical conditions. First, the injured neuron must respond to axon interruption by initiating a program of gene expression that can support axon elongation. Many of the genes involved in the outgrowth of axons over long distances during embryonic development (see Chapter 23) are not normally expressed in adult neurons. Interruption of axons reactivates expression of some of these genes in the peripheral nervous system, but not in the adult CNS. Axons damaged in the long tracts of the brain or spinal cord, particularly at sites far from their cell bodies, rarely re-express these genes. Second, once a damaged neuron initiates a genetic program that can support axon regrowth, the emerging growth cones must encounter an environment that can support and guide the regrowing axons. In peripheral nerves, damage or degeneration triggers changes that produce a favorable environment for axon elongation. Schwann cells and other non-neuronal cells respond to axonal injury by elaborating cell adhesion molecules, extracellular matrix components, and an array of neurotrophins and other signals that promote axon growth (see Chapter 23). Equally important, damaged peripheral nerves are invaded by macrophages that rapidly remove fragments of degenerating axons and myelin that might otherwise inhibit the growth of regenerating axons.

In contrast, damage to axonal tracts in the adult CNS triggers a very different set of changes. As axons and their myelin sheaths break down, the remnants are not cleared efficiently and can persist for many weeks, posing a substantial impediment to regeneration. This inhibition appears to reflect the activity of a protein called Nogo that blocks axon extension by interacting with advancing growth cones (see Box D). Nogo is produced by oligodendrocytes, the glia that normally form myelin sheaths around CNS axons. To make matters worse, astrocytes reacting to CNS injury express additional inhibitors of axon extension. As a consequence, even if a central neuron initiates a genetic program for regeneration, growth cones emerging from the site of a lesion in the adult CNS encounter an array of circumstances that impede recovery.

Box D

Why Aren't We More Like Fish and Frogs?

The role of the axonal environment in regeneration of CNS axons was explored by Albert Aguayo and his co-workers at McGill University in the 1980s. They grafted segments of peripheral nerve into sites in the CNS, such as optic nerve, spinal cord, or other locations, and then determined whether neurons were able to regenerate axons through the peripheral grafts. Their studies showed that at least some CNS axons are able to take advantage of the more supportive growth environment of the peripheral nerve, regenerating over distances of many centimeters and in some cases restoring appropriate synaptic connections (see Box D).

This demonstration that CNS axons can sometimes regenerate successfully into a peripheral nerve graft sparked intensive efforts by many labs to produce a similarly supportive environment for axon growth within the long tracts of the brain or spinal cord. For example, Martin Schwab and his collaborators showed that implanting cells engineered to secrete antibodies against inhibitory proteins, including Nogo, alleviated some of the inhibitory properties of CNS myelin in experimental animals. Another approach was to introduce cells that provide a more supportive environment for regenerating axons in the damaged CNS. Schwann cells, neural stem cells (see next section), and specialized glial cells from the olfactory nerve all can be grown in tissue culture and introduced into the brains or spinal cords of experimental animals, where they modestly improve axon regrowth and, in some cases, functional recovery.

In summary, regeneration in adults is held in check by ongoing suppression of genes required for effective axon elongation. Injury to the peripheral nervous system readily induces expression of this genetic program, while interruption of mammalian CNS axons does not. Once CNS neurons have activated these genes, in principle regrowth could be enhanced by removal or neutralization of inhibitory molecules, and by the introduction of cells that provide a more supportive growth environment. These strategies, however, have not been proven clinically useful. Why this patently maladaptive state of affairs has persisted in evolution is much debated (Box D).