Brain-injury rehabilitation depends on acetylcholine circuitry

The ability of the brain to recover from such injury as stroke or trauma depends on a particular circuitry of neurons that "talk" to one another using the brain chemical acetylcholine, researchers led by James Conner and Mark Tuszynski in the Neural repair Group at UCSD have discovered. Their finding in rats could help enhance rehabilitation to recover from such injuries by leading to the development of drugs or other treatments to enhance the "cholinergic system."

The researchers said that their finding that the cholinergic system is involved in brain recovery is particularly intriguing in light of the fact that deficits in the system have been associated with aging, Alzheimer's disease, and traumatic brain injury.

Researchers have long believed that rehabilitation from brain injury causes a rewiring, or plasticity, of brain circuitry--called a "reorganization of cortical motor representations"--to reestablish connections that control muscles. However, the specific type of brain circuitry on which this plasticity depended was not known.

Conner and his colleagues were guided in their experiments by earlier studies showing that the cholinergic system in a region called the basal forebrain was associated with normal learning of motor control.

To determine whether this same system also played a role in rehabilitation from brain injury, they first taught rats to reach for food pellets with their forepaws. In one group of animals, they then used a toxin to specifically eliminate cholinergic nerves connecting to the motor and sensory regions of the animals' cortex. The other control group received a sham injection. The researchers then used electrical probes to create small lesions in the rats' brain region responsible for controlling limb movement.

They then gave the rats rehabilitation training. The control group of rats recovered about 55% of the deficit in their reaching ability, while the rats lacking a cholinergic system recovered only about 18%.

In other experiments, the researchers compared the plasticity of brain reorganization in a brain region known to be "cholinergic independent" with the area governing forelimb control, which was "cholinergic dependent." They found that the former region did not require rehabilitative training to reorganize itself.

"Identifying neuronal mechanisms underlying the reorganization of cortical representations will likely be an important precursor for designing therapeutic strategies to enhance functional recovery following nervous system injury," the researchers wrote. "The present study makes a significant contribution toward this goal by identifying the basal forebrain cholinergic system as an essential substrate in mediating cortical plasticity and functional recovery following focal cortical injury."

They also concluded that drugs that inhibit breakdown of acetylcholine or those that encourage brain wiring growth "may enhance cortical plasticity and improve functional recovery following nervous system injury."

The researchers also noted that brain circuitry that depends on other types of neurotransmitters such as noradrenalin, dopamine, or serotonin have also been implicated in cortical plasticity and may also be manipulated to aid recovery after such injury.