Adult neurogenesis is implicated in both normal neurobiological processes such as learning and memory, and in contributing to pathological states in its dysfunction. This process is regulated by experience and neuronal activity (activity-dependent adult neurogenesis) through local and long-distance connections. However, the mechanisms that underly activity-dependent adult neurogenesis are poorly characterized, and this has impeded efforts to determine whether adult neurogenesis is causally linked to linked to processes such as learning and memory, or diseases such as epilepsy and schizophrenia. I have identified the neuropeptide cholecystokinin (CCK) as a putative regulator of adult neurogenesis. My preliminary data suggests adult neural stem cells express functional CCK2 receptors, and that activity of CCK-expressing neurons could promote the proliferation of adult neural stem cells and neural progenitors. In order to further investigate these findings, I will utilize a combination of in vivo manipulations, viral techniques, and immunohistochemistry to activate these cells and determine their influence on the proliferation of adult neural stem cells and neural progenitors, the survival of neural progenitors and immature neurons, and the maturation and integration of maturing newborn neurons. In addition, I will learn calcium imaging and electrophysiology techniques to study how CCK-cell activity acts on these developing cells. Finally, I will train in advanced microscopy techniques in order to quantify these effects. With these techniques, I will exhaustively characterize the influence of CCK-cell activity on these stages of adult neurogenesis. Understanding this process could also lead to advancements in treating neurodegenerative disorders, such as facilitating the the proliferation, maturation, and integration of transplanted neural stem cells in order to treat conditions such as traumatic brain injury. Understanding trophic signals (such as CCK) that promote proliferation, survival, and integration of newborn neurons could advance the effectiveness of this putative therapy. Taken together, this proposal will address a basic fundamental gap in neurobiology, as well as providing potentially translational findings for human therapeutics.
It has become increasingly clear that adult hippocampal neurogenesis is significantly regulated by neuronal activity, but our limited understanding of this regulation and the systems involved has restricted our ability to definitively parse the contribution or importance of this process to normal function and its role in neurological dysfunction. The proposed studies will utilize a combination of genetic and chemical approaches to study the role of the neuropeptide cholecystokinin in the modulation of adult hippocampal neurogenesis in a mouse model. As few neurotransmitter systems have been exhaustively studied in the regulation of neurogenesis, results from this project will contribute to filling a significant gap in our understanding of this enigmatic neurobiological process.
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