Neural Mechanisms of Compensating for Brain Damage

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DESCRIPTION (provided by applicant): A reliable consequence of survivable brain damage is that animals, including humans, learn compensatory behavioral strategies for resuming daily activities in the presence of lost function. An obvious example of this can be found in clinical stroke populations with upper extremity impairments in their reliance on the less- affected (nonparetic) hand and arm. The focus of this project across periods has been on the interactions between such compensatory behavioral changes and injury-induced degenerative and regenerative responses. This is investigated in a rat model of chronic upper extremity impairments and compensatory skill learning after focal ischemic damage to motor cortex. We've previously found that, as a result of its interaction with ischemia-triggered regenerative responses, learning to rely on the nonparetic forelimb promotes a major neuronal growth response in the contralesional motor cortex, a response that has no known benefit for the paretic forelimb, but facilitates compensatory skill learning with the nonparetic limb. In the most recent project period, we discovered that the same skill learning that promotes this contralesional growth response also exacerbates dysfunction in the paretic hand, and blocks the cortical structural and functional reorganization in the injured hemisphere that can mediate its functional improvements. The implication is that, simply by adopting perfectly reasonable strategies for resuming everyday activities, some stroke survivors could inadvertently squelch the paretic hand's potential for functionality. The goal for the proposed studies is to understand the mechanisms of this disruption of the functional potential of the paretic limb. We see in the pattern of our results reflections of "experience-expectant" plasticity, a brain developmental process that relies on experiences to sculpt circuitry patterns using mechanisms of activity-dependent synaptic competition. The purpose of this project is to determine whether the maladaptive effects of learning to rely on the nonparetic forelimb are due to its ability to outcompete with the paretic limb in driving the direction of post-ischemic reorganizational patterns. We will use a hypothesis-driven approach in combination with behavioral- and cortical-level manipulations to test for experience- and activity-dependent competition in circuitry remodeling of the converging projections of the ipsi and contralesional hemispheres to regions denervated by the injury. The specific aims are to test the hypotheses that skill learning and "re-learning" with the nonparetic and paretic forelimbs drive different reorganizational patterns within peri-infarct MC (Aim 1) and of corticofugal projections (Aim2), that the nonparetic limb's disarray of peri-infarct reorganization can be overcome by balancing motor cortical (Aim 3) and behavioral activity (Aim 4) and that these effects depend on the specific territory of the injuries (Aim 5). These studies are significant for advancing our basic understanding of the mechanisms of brain reorganization after stroke and, ultimately, for informing therapeutic decision on when to promote or discourage behavioral compensation.