Adult neural circuits are in a state of constant remodeling. One of most striking mechanisms by which this occurs is the insertion of new neurons, a process that occurs normally in all adult mammals and has been hypothesized to underly aspects of physiological information storage. Abnormal adult neurogenesis, by contrast, has been linked to major neuropsychiatric diseases including drug addiction and depression. We have found that neural activity acts directly on proliferating progenitors to drive adult neurogenesis, and recent years have witnessed many other important new insights into the underlying molecular mechanisms. However, little or no insight has emerged into the impact of adult neurogenesis on neural circuit function. We propose to apply novel ion channel-based probes to study interactions between CMS circuits and calcium channel-dependent neurogenesis. We hypothesize that circuit activity acting through calcium channels is a crucial component of the cellular microenvironment controlling adult neurogenesis. We further hypothesize that this is a bidirectional interaction, as newborn neurons (once functionally inserted into the circuit as a result of local activity patterns) in turn directly modulate these local network activity patterns.
Aim 1 will identify mechanisms by which activity and cellular microenvironment interact to drive calcium channel-dependent adult neurogenesis.
Aims 2 and 3 will explore mechanisms by which newborn neurons in turn modulate circuit activity dynamics, using novel high-temporal resolution imaging (Aim 2) and stimulation (Aim 3) techniques.
Aim 4 describes use of a new genetically-encoded light-responsive stimulation tool to provide physiological activity patterns to proliferating progenitor cells, in order to study molecular mechanisms of environmental control of excitation-neurogenesis coupling. Together, insights garnered from determining the reciprocal relationship between circuit activity and adult neurogenesis may profoundly illuminate core mechanisms of hippocampal neuropsychiatric disease and suggest novel therapeutic strategies, while deepening our understanding of the normal activity-dependent operation and plasticity of progenitor cells in the hippocampal circuit.
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