Introduction: Post-stroke brain stimulations are promising neurorestorative techniques as they allow direct manipulation of the target area’s excitability. Previously we demonstrated that optogenetic neuronal stimulation of the ipsilesional primary motor cortex promotes functional recovery. To determine an optimal brain stimulation target, we tested whether optogenetic neuronal stimulation of the contralesional cerebellar dentate nucleus (cDN) can promote recovery. We hypothesized that stimulation of cDN may be more effective, as it sends excitatory outputs to multiple cerebral regions.
Methods: Thy-1-ChR2-YFP line-18 transgenic mice underwent stereotaxic fiber cannula implant in cDN, followed by transient middle cerebral artery occlusion. Control non-stimulated mice, short-term stimulated mice (day5-14) and long-term stimulated mice (day5-28) were used. Sensorimotor behavior tests were used to assess their recovery at day 0, 4, 7, 10, 14, 21 and 28 post-stroke. Mice were sacrificed at various timepoints for immunohistochemistry and western blots.
Results: Our data showed that stimulated stroke mice recovered with significant improvement in distance traveled (p<0.01) and faster speed on the rotating beam at day14 post-stroke (p<0.05). The short-term stim group continued to recover after day14 without further stimulations and the long-term stim group did not showed additional enhanced recovery, indicating that functional outcome of cDN stimulation is persistent. Western blotting showed that stimulated stroke mice exhibited a significant decrease in pCREB and total CREB expression in ipsilesional M1 (p<0.01) and an increase in GAP43 expression in ipsilesional S1 (p<0.05).
Conclusions: Our data suggest that cDN stimulations post-stroke can promote functional recovery and this pro-recovery effect is persistent. Recovery of cDN-stimulated stroke mice is associated with up-regulation of plasticity marker GAP43 and down-regulation of CREB signaling. Current studies examine the effects of cDN stimulations on axonal sprouting and the contribution of CREB in recovery. cDN could be a promising brain stimulation target for stroke recovery.
Patient Care: Provide new treatment strategy for stroke patients using deep brain stimulation.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of certain neuronal circuit for stroke recovery, 2) Identify an effective treatment for stroke disability.