Optogenetic Stimulation of the Lateral Cerebellar Nucleus Mitigates Stroke-Induced Disruption of Motor Cortex Activity and Behavior

Stroke causes severe motor deficits, but functional recovery can occur through neural circuit reorganization in areas adjacent to and remote from the infarct. Optogenetic stimulation can modulate neuronal activity and improve recovery in experimental models, but the cellular and circuit mechanisms remain unclear. We investigated longitudinal changes in neuronal activity in ipsilesional primary motor cortex (iM1) using in vivo Ca²⁺ imaging in mice receiving optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN) following ischemic stroke. Stroke decreased iM1 excitability, altered population-state distributions, and disrupted coordinated population activity. cLCN stimulation was associated with restoration of population activity at early post-stroke timepoints and preserved network connectivity associated with behavioral performance. Despite heterogeneous neuronal responses, the net effect of cLCN stimulation was an earlier return of iM1 dynamics toward pre-stroke patterns. These findings define population-level iM1 changes after stroke and support the cLCN as a neuromodulatory target for restoring cortical activity.