Research Project
10300707
Stroke remains the leading cause of motor disability in the United States; there are no current therapies known to reliably improve recovery. A few clinical studies have suggested that sleep may play an important role in determining outcomes after injury and further in optimizing the effects of rehabilitation. Importantly, there is a growing body of literature highlighting that offline processing during sleep can improve motor performance. However, what/how sleep stages contribute to motor recovery after stroke/brain injury remains unclear. Using long-term large-scale electrophysiology monitoring, closed-loop stimulation (CLS), and cell-type-specific neural modulation in rats stroke models, I aim to manipulate sleep-dependent cortical processing that can enhance the motor recovery post-stroke. To implement a CLS, I will delineate a timing of sleep that can optimally promote motor recovery, elucidate underlying neural mechanisms, and test if brain state based CLS during offline processing can enhance motor recovery. Mentored Phase: the objective is: (1) to find RESEARCH the timing of sleep and mechanisms that can serve as optimal triggers for CLS, and (2) to test if CLS to the perilesional cortex (PLC) during sleep promotes the recovery. My pilot experiments in rats stroke models suggest that the temporal interactions of spindles to slow-waves (i.e. slow-oscillations/SO and delta-waves) during NREM sleep may be an important biomarker of recovery. I will find a more precise mechanism of offline recovery processing and test the effects of CLS modulating either spindles' timing or excitability during spindles. Independent Phase: Top-down intracortical transfers, e.g. prefrontal cortex (PFC) to the motor area, are closely related to sleep-dependent memory processing and similar hierarchical flows are observed in SO. This inter- regional interaction is also linked to interneurons' activity. Using transgenic rats (PV-Cre) with stroke, I will: (3) find an optimal timing/rate of inhibitions for offline recovery processing and test effects of CLS enhancing PFC- PLC interactions during SO. These will combine multi-resolution electrophysiology (spikes, local-field potential, and electrocorticography) and state-of-the-art optical monitoring. While I propose the approach by optogenetics technique, I also seek to identify alternative modulation methods (e.g. GABAA receptor blocker) that might be identified through more clinical means and synergistic combinations with the CLS paradigm for stroke recovery. My long-term goal is to become an independent investigator focusing on advancing new neurotechnologies that target modulating brain computation and facilitate motor control, especially during recovery from an injury. In this project, I will (1) gain expertise in multi-site long-term recordings and stimulation, (2) acquire further proficiency in new-fashioned data analyses, (3) gain expertise in simultaneous neural manipulations, physiology, and optical recording and more invasive rodent stroke models, (4) improve knowledge in the clinical aspects, (5) obtain an independent tenure-track assistant professor position and transfer to the R00 portion within 2 years, and, (6) to obtain R01 funding within 5 years of this proposal.
