AN INTEGRATED VIEW OF NEURAL REPAIR AFTER STROKE

Stroke triggers physiological and structural changes in neuronal circuits adjacent to the infarct. These changes affect stroke recovery and can be manipulated to lead to neural repair. Neuroplasticity after stroke includes the formation of new connections in cortex adjacent to the stroke site (termed axonal sprouting), the formation of new neurons and their migration to areas of injury (termed post-stroke neurogenesis), the recruitment and differentiation of immature forms of glial cells (oligodendrocyte precursor cells, OPCs) and physiological changes in the responses of cortical circuits (post-stroke hypoexcitability). The Carmichael lab has active projects in all four of these areas, and in determining how stem cell transplants in stroke interface with the normal, or endogenous, neuroplasticity to promote recovery.
 
A key aspect of neural repair after stroke is that none of these cellular and molecular events are occurring in isolation. Axonal sprouting after stroke means that neurons are induced into a growth state, but encounter growth inhibitory molecules. This is sort of a yin/yang of in axonal sprouting, and evidence is emerging that a focus on just one aspect, such as blocking growth inhibitors, is not enough to induce functional recovery.  In post-stroke neurogenesis, migrating immature neurons preferentially associate with angiogenic blood vessels, forming a neurovascular niche. Neurogenesis and angiogenesis are integrated tissue reorganization processes after stroke.

Neural repair after stroke also occurs within a time spectrum, from the initial damage of the stroke itself and extending to later phases of recovery. Events that promote repair and recovery later in stroke might exacerbate the initial stroke damage early in this spectrum. This is another example of a yin/yang in stroke: cellular processes that initially protect the brain from further injury actually impair recovery if they persist for too long. We have shown this to be the case with tonic GABA inhibitory signaling.

Finally, the events that underlie neural repair after stroke are occurring within an injured brain that exhibits altered behavioral and neuronal activity patterns. The stroke itself causes alterations in movement, sensation, language and cognition, and impairments in these functions alter the normal neuronal activity patterns in these brain areas. If these areas are also undergoing axonal sprouting or neurogenesis, then the impaired activity patterns after stroke may impact these two neural repair processes. Neurorehabilitation after stroke imposes still other patterns of behavioral activity on the injured and reorganizing brain. Physical therapists work with stroke patients to increase walking and train the gait cycle; occupational therapists stimulate repetitive arm movements. These behavioral activity patterns directly influence brain maps, and alter, for example, angiogenesis and axonal sprouting.

The important aspect of all these interactions is that neural repair after stroke is an integrated process of activity, physiological plasticity, molecular growth and inhibitory programs, vascular remodeling and stem cell responses. A human therapy that repairs the brain after stroke will need to be developed with an integrated view
of neural repair.