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Optogenetic neuronal stimulation promotes functional recovery after stroke

Significance Stroke is the leading cause of disability in the United States and has very limited treatment options. Brain stimulation techniques that promote recovery after stroke are a promising area of research; however, current stimulation techniques nonspecifically activate/inhibit the target area, which not only leads to undesired side effects but also makes it difficult to understand which cell types and mechanisms drive recovery. We used the optogenetic technique to specifically stimulate only neurons after stroke and demonstrate that selective neuronal stimulations can activate beneficial mechanisms and promote recovery. Understanding the cell type and mechanisms driving recovery may identify potential drug targets for stroke treatment, as well as ultimately help develop precise brain stimulation techniques for stroke therapy. Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area’s excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.