Induction of Neurogenesis in Neocortex for Brain Repair

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DESCRIPTION (provided by applicant): The long-term goal of the proposed experiments is the repair of damaged neocortical circuitry. Much of our prior work has focused on repair by transplantation of immature neurons and neural precursors. Recently, however, we have manipulated endogenous precursors in situ in the adult mouse to undergo neurogenesis and anatomic circuit re-formation de novo in the neocortex, where it does not normally occur, This was without transplantation. This work aims toward the ultimate goal of repair by manipulation of endogenous neural precursors in situ. This could lead to therapies for degenerative, developmental, or acquired diseases of cortex and its output circuitry (e.g. spinal cord). In neocortex, the effectiveness of such future therapies could depend critically on whether endogenous precursors, or stem cells, can be precisely induced to form new neurons; migrate to correct locations; differentiate and integrate appropriately; and re-form precise long-distance projections and complex functional connections. Neuroblasts and neural precursors respond specifically to altered expression of local signal molecules in regions of cortex undergoing synchronous biophysically-induced apoptosis of projection neurons. They selectively migrate into such regions, differentiate into projection neurons, receive synaptic input, and re-form long-distance circuitry. Though we have made considerable progress in identifying conditions under which cortical neurogenesis and partial repair of cortical circuitry is possible in the adult, many questions still remain to be investigated. These questions form the basis of the proposed research: 1) Can we substantially increase the number of new cortical neurons by manipulating proliferation/differentiation of endogenous precursors &/or survival of newborn neurons? 2) Can newborn neurons differentiate precisely into new functional projection-neurons, receive afferent synapses, and become functionally integrated? 3) What are the molecular mechanisms responsible for inducing neurogenesis and specific differentiation by endogenous precursors in the adult neocortex? Our three specific aims will test and investigate these questions directly. Proposed experiments will: Aim 1) determine the effects of select candidate growth factors toward increasing the amount of induced neurogenesis in neocortex of adult mice; Aim 2) investigate the precision of newborn neuron differentiation by analysis of neurotransmitter and receptor complement and synaptic integration, using confocal and immunocytochemistry; and Aim 3) investigate the molecular mechanisms of this induced neurogenesis via microarray analysis of differential gene expression, confirmation of candidates, and in vitro functional assay. Together, these experiments will investigate the molecular mechanisms underlying induced neurogenesis in the adult murine neocortex; the potential for substantially increasing the amount of neurogenesis; and the ability of newborn cortical neurons derived from endogenous precursors to repair cortical circuitry.