DESCRIPTION (provided by applicant): The hippocampus is one of a select few brain regions that retain the ability to generate neurons in adulthood. The conservation of adult neurogenesis across mammalian species from mice to humans suggests that neurogenesis contributes to hippocampal function in significant ways. Indeed, research in human patients and animal models suggests that changes in neurogenesis alter memory function and contribute to the etiology and treatment of emotional disorders. If we are to understand how the hippocampus mediates memory, emotion, and disorders thereof, we must understand the role of adult neurogenesis in hippocampal function. The main goal of this project is to identify mechanisms through which adult-born neurons contribute to hippocampal mechanisms of memory. We will focus on one well-studied model of neurogenesis-dependent learning: contextual fear conditioning, a ubiquitous form of learning in which animals acquire fear of a context paired with aversive stimulation. We have shown that arresting adult hippocampal neurogenesis impairs contextual fear conditioning, in that mice without neurogenesis exhibit less learned fear of a shock-paired context. However, the simple observation that arresting adult neurogenesis impairs CFC reveals very little about the role of adult neurogenesis in hippocampal memory mechanisms. Addressing mechanistic questions about the role of neurogenesis in memory processes requires new methods of manipulating neurogenesis with temporal and cellular precision. To this end we developed two new methods of manipulating neurogenesis with high temporal and cellular specificity. One is a novel transgenic mouse that enables reversible ablation of neural progenitor cells. The other is combined transgenic/viral approach that expresses an optogenetic neural silencer in defined cohorts of adult-born neurons. We propose to use these methods to reveal how neurogenesis contributes to underlying memory processes, such as acquisition, systems consolidation, and retrieval. Specifically, we will address these critical questions about the role of young, adult-born neurons in contextual fear memory: (1) Does the role of adult-born neurons in contextual fear conditioning relate to context representation, emotional learning, or expression of these forms of learning? (2) How does addition of neurons to the hippocampus affect maintenance of existing contextual fear memories? (3) What role do adult-born neurons play in long-term retention of the memories they help encode? These studies will elucidate fundamental mechanisms through which adult neurogenesis modulates memory, and, in doing so, will clarify mechanisms through which alterations in neurogenesis contribute to the treatment and etiology of emotional disorders, such as depression and anxiety disorders. 0925-0001/0002 (Rev. 08/12) Page Continuation Format Page

PUBLIC HEALTH RELEVANCE: This research will improve our understanding of how adult neurogenesis -the birth of neurons in the adult brain- affects memory processing in the hippocampus. Research in human patients and animal models suggests that changes in neurogenesis alter memory function and contribute to the etiology and treatment of emotional disorders. Using new genetic tools to manipulate adult neurogenesis in temporally precise ways, we will determine how adult-born neurons contribute to acquisition, maintenance and retrieval of memories. By clarifying how adult hippocampal neurogenesis modulates memory processes, this research will elucidate mechanisms through which alterations in neurogenesis contribute to the treatment and etiology of emotional disorders. 0925-0001/0002 (Rev. 08/12) Page Continuation Format Page