Molecular Mechanisms of Axonal Sprouting and Recovery from Stroke

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DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability. However, a limited and spontaneous process of repair and recovery does occur after stroke. In stroke patients this recovery is associated with re-mapping of sensory and motor functions in peri-infarct and connected cortical areas. In non-human primate and rodent models, stroke induces new connections to form in these same areas, by a process termed axonal sprouting. We have recently shown that in a mouse model of stroke, axonal sprouting in motor and premotor cortical circuits after stroke is causally associated with motor recovery. These studies identify axonal sprouting as an important cellular target in promoting enhanced recovery after stroke. The process of axonal sprouting after stroke involves three key steps for an adult cortical neuron: stroke sends a signal to adjacent neurons (a trigger), which activates a gene expression program (transcription factor), and the neuron then initiates axonal growth through the brain (extracellular signaling or adhesion proteins). We have recently identified a "sprouting transcriptome" of successfully sprouting neurons in peri-infarct cortex after stroke. When this transcriptome is analyzed with stringent statistical testing, and the genes associated with routine cytoskeletal structure removed, a small set of molecules are linked to the process of sprouting in neurons after stroke. Three molecules are highly regulated in sprouting neurons in relationship to these three key cellular steps in post-stroke axonal sprouting. Growth Differentiation Factor 10 (GDF10) is a bone morphogenic protein that is secreted after stroke (potential trigger). Bcl11b is a transcription factor that is also induced in sprouting neurons and has a normal function of promoting cortical axon growth in the developing brain. Matrilin-2 is an extracellular matrix protein that promotes peripheral nerve regeneration and is paradoxically down-regulated in cortical sprouting neurons after stroke. GDF10, Bcl11b and matrilin-2 have not been studied extensively in the adult brain, and have not been studied at all after stroke. Preliminary data links these three molecules to axonal sprouting in vitro and in vivo. The studies in this grant wil use pharmacological and genetic manipulation techniques to determine if these three molecules induce axonal sprouting, and then determine the patterns of motor and sensory maps in the living mouse over time that are associated with gain and loss of function in these molecular systems. Finally, the effect on motor control and recovery after stroke with gain and loss of function in these systems will be determined. This approach uses a novel experimental platform of detailed and structural mapping of brain connections, in vivo mapping of the functional physiology of these connections, and behavioral studies of recovery, for a "molecules to maps to behavior" approach to confirm highly promising molecular targets for post-stroke neural repair.