The goal of this K25 Mentored Career Development Award is to provide the candidate (a Ph.D. in experimental physics) with the necessary training in neuroscience, and mechanisms of brain injury and repair to launch an independent career studying stroke recovery. Washington University School of Medicine will provide an ideal setting for the candidate's training by providing them access to some of the leading medical and biomedical collaborators in the fields of brain function, functional imaging, stroke, and stroke recovery. The proposed research, which will be conducted under the co-mentorship of Drs. Jin-Moo Lee and Joseph Culver, will examine the role of network connectivity and perilesional activity on cortical plasticity and behavioral recovery using a mouse model of ischemic stroke. Current research suggests that complex behaviors rely on distributed network interaction; disruption in these neural networks, for example by stroke, has consequently been shown to alter brain function and behavioral outcome. However, what is much less clear is the impact of altered networks on behavioral and functional recovery after brain injury. There is accumulating evidence that physiological activity (through use of the impaired modality) enhances recovery; it follows that network connectivity in the brain (or lack of) may have profound influences on stroke recovery mechanisms. Understanding the implications of network structure and activity on stroke recovery, and then potential therapeutic approaches, will require mechanistic studies linking functional connectivity (fc) measures to network manipulations during the recovery period. Towards this goal, this grant proposes to take advantage of two novel technologies, functional connectivity optical intrinsic signal imaging (fcOIS, co-developed by the candidate), which for the first time allows fc imaging in mice, and ontogenetic. This proposal will test the hypothesis that chronic, intermittent activation or inhibition of local or distant brain circuits modulates network plasticity following focal ischemic injury through the following Aims: 1) Evaluate the time-course and evolution of network fc, functional remapping, and behavioral recovery following photothrombotic infarction of the forepaw somatosensory cortex (S1fp). 2) Determine the selective influence of perilesional inhibitory interneuronal activity on fc, remapping, and behavioral recovery after S1fp photothrombosis. 3) Determine the selective influence of contralesional homotopic input to perilesional cortex on fc, remapping and behavioral recovery after S1fp photothrombosis. Results from the proposed studies could have implications for the design of interventions to promote recovery following human stroke: either through direct non-invasive brain stimulation or through optimization of physiologic therapeutic maneuvers (e.g. forced-use therapies designed to enhance plasticity through stimulation of the brain's natural recovery mechanisms.
According to the American Heart Association, stroke is the fourth leading cause of death and the leading cause of adult disability in the US, with an annual stroke incidence of 780,000 strokes. It is clear that strokes disrupt brain function and result in behavioral deficits; however, many stroke survivors exhibit some level of recovery, even in the absence of directed therapy or rehabilitation. In this K25 proposal, we will investigate how network activity influences behavioral and functional recovery after ischemic stroke.
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