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.