Abstract 69: Cerebellar Dentate Nucleus is an Effective Brain Stimulation Target for Post-stroke Recovery

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Objective: Functional recovery after stroke has been observed in both human and animal studies. Post-stroke brain stimulations are promising neurorestorative techniques as they allow direct manipulation of the target area’s excitability. Previously we have demonstrated that optogenetic neuronal stimulation of the ipsilesional primary motor cortex (iM1) promotes functional recovery. To determine an optimal brain stimulation target, we test whether optogenetic neuronal stimulation of the contralesional cerebellar dentate nucleus (cLCN) can promote recovery. We hypothesize that stimulation of cLCN may be more effective, as it sends excitatory outputs to multiple motor and premotor areas.Methods: Thy-1-ChR2-YFP line-18 transgenic male mice were used. Mice underwent stereotaxic surgery to implant an optical fiber in cLCN or iM1, followed by an intraluminal middle cerebral artery suture occlusion. Three groups of mice were used: control non-stimulated stroke mice, short stimulated stroke mice (short-stim, day5-14 post-stroke) and long stimulated stroke mice (long-stim, day5-28 post-stroke). Sensorimotor behavior tests were used to assess their recovery.Results: Our data showed that cLCN-stimulated stroke mice recovered quickly, with significant improvement in distance traveled as early as day7 (p<0.05), and faster rotating beam spole speed at day14 post-stroke (p<0.001). The effect of cLCN stimulation was persistent, as the short stim group continued to recover after day14 without further stimulations. The long stim group did not further enhance recovery. Interestingly, cLCN-stimulated mice performed significantly faster than iM1-stimulated mice. Analysis of pCREB activation showed that cLCN stimulation activates the dentatothalamocortical pathway.Conclusion: Our data suggest that cLCN stimulations post-stroke can promote persistent functional recovery. Furthermore, cLCN-stimulated mice recovered faster than iM1-stimulated mice, indicate that cLCN may be a more effective brain stimulation target. Current studies examine the brain activation patterns of cLCN-stimulated mice, as well as the mechanisms of cLCN-induced recovery.

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