This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed study reflects the interdisciplinary collaboration between the laboratories of Drs. McNeill, Jones and Schallert that will further our understanding of the cellular and molecular events underlying the synergism between neural plasticity and treatment strategies that promote the recovery of function after brain damage. The experimental design integrates the research expertise on the cellular mechanism of neural plasticity from McNeill''s laboratory with that of Jones and Schallert, who have examined the influence of behavioral experience on neural plasticity and recovery of function after ischemic brain injury. The goal of the study is to determine whether rehabilitative training can enhance neurite outgrowth and gene expression of candidate molecules involved in reactive synaptogenesis and identify key molecules that can serve as the focus for the development of new and innovative approaches in stroke rehabilitation. The rationale for the study is based on previous studies from the investigators'' laboratories, as well as those of others, who have reported that: 1) neural plasticity plays a critical role in the recovery of function after ischemic brain injury, 2) rehabilitative training can enhance the recovery of function after stroke, 3) cortical reorganization and synapse replacement after brain injury involves the differential regulation of specific sets of growth-associated proteins, neurotransmitters and neurotrophins that are lesion-specific, and 4) nigrostriatal neurons that contain both dopamine and brain-derived neurotrophic factor (BDNF), a molecule essential to neuron survival and synapse function, are essential for the maintenance of corticostriatal synapses on striatal target neurons after brain injury. The overarching hypotheses to be tested are: 1) that adjunctive use of rehabilitative training enhances the upregulation of molecules known to modulate neurite outgrowth and spine density in neurons of the cortex and striatum; and 2), that these interventions converge on intracellular siqnaling pathways associated with monoamine activation and BDNF upregulation for their therapeutic effect.
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