A Neurophysiological Approach to Post-Stroke Motor Recovery - Project Summary Stroke is a leading cause of disability in the United States. While there have been advancements in neurorehabilitation strategies, many patients continue to suffer from chronic disability, underscoring the need for further research into novel approaches to rehabilitation. Sleep remains relatively understudied in stroke studies even though there is evidence that lack of sleep following a stroke worsens neurological symptoms and long-term outcomes. Thus, sleep may be a useful target in developing new rehabilitation strategies. We propose to study the cortical and cerebellar regions during sleep to elucidate the systems-level neural processing that is linked to performance gains during the recovery period. Our recent work has shown that non-rapid eye movement (NREM) sleep processing in the motor cortex (M1) of healthy rats is linked to performance improvements in a motor task. Additionally, it is widely acknowledged that motor learning of clinically important and continuous movements has cerebellar correlates. Interestingly, recent work has shown that NREM sleep spindles have a cerebellar origin. Sleep spindles are widely known to be involved in reactivating awake learning activity, but these studies have more commonly focused on the neocortex, hippocampus, and thalamus. However, the extent to which NREM spindle oscillations in the cerebellum covary with the spindle oscillations in the neocortical regions (and if they reactivate awake single neuronal activity in both regions) during sleep to improve performance remains incompletely understood. Moreover, it is key to understand the sleep stages and accompanying neurophysiology that support post-stroke motor recovery in these structures, as well as the extent to which they can be modulated to enhance recovery. In this proposal, we take a systems-level approach to: (i) understand the coordinated NREM sleep processes in cortico-cerebellar networks that are associated with motor learning/ recovery in intact and stroke-injured rats, specifically if spindle activity is temporally locked in these regions; (ii) establish necessity of NREM sleep- related neural processing in skill consolidation and recovery through optogenetics; and (iii) test if augmentation of these sleep-related neural events using electrical stimulation of cerebellum enhances recovery. We will use simultaneous large-scale electrophysiologic monitoring of cortico-cerebellar networks with electrical stimulation and optogenetics in a rodent stroke model to test the following hypothesis: coupled NREM sleep activity in the intact and ipsilesional spared M1 and contralateral cerebellar cortex underlies motor learning or recovery after stroke, learning is reduced when this synchronization is disrupted via optogenetic inhibition of the cerebellar activity, and learning is increased when this synchronization is boosted via electrical stimulation of the cerebellum.
