PROJECT SUMMARY The overall goal of the proposed research is to determine the effect of pharmacological, genetic, or activity - based intervention to restore the neurogenic response to enriched environment (EE) in a mouse model of prenatal alcohol exposure (PAE). If successful, these studies may provide potential avenues of intervention for hippocampal dysfunction associated with fetal alcohol spectrum disorder (FASD). The current proposal is designed to test the overall hypothesis that increasing the survival of newborn neurons will reinstate the neurogenic effect of enrichment in PAE mice. This proposal is premised on prior work demonstrating that gestational exposure to moderate levels of alcohol have no effect on adult hippocampal neurogenesis when mice are housed under standard conditions, but markedly impairs the ability of mice to mount a neurogenic response to social and physical environmental enrichment. This impairment is not the result of reduced proliferation or size of the progenitor pool, but results from impaired survival of newborn dentate granule cells (nDGCs) during the activity-dependent stage of circuit integration. Using a well-characterized limited access voluntary drinking paradigm, I will test our overarching hypothesis by addressing the following specific aims: Specific Aim 1: To determine the therapeutic potential of fluoxetine (FLX) to restore EE-mediated neurogenesis in PAE mice. For these studies, I will chronically administer the SSRI antidepressant, fluoxetine, (previously documented to enhance the survival of nDGCs), during EE to determine its effects on the neurogenic response in PAE mice. In addition, I will correlate the neurogenic response with behavioral assays of hippocampal function. Specific Aim 2: To determine the therapeutic potential of apoptotic inhibition, using inducible BAX knockout mice, to restore EE-mediated neurogenesis in PAE mice. I will utilize a genetic approach to prolong the survival of nDGCs in PAE-EE mice. Specifically, I will generate and characterize a triple transgenic mouse line, NestinCreERT2:tdTomato:BAXf/f, to test whether selective deletion of the pro-apoptotic gene, BAX, within hippocampal progenitors and their downstream progeny will facilitate EE-mediated neurogenesis in PAE mice. Specific Aim 3: To determine the therapeutic potential of chemogenetic activation of nDGCs, to restore EE-mediated neurogenesis in PAE mice. Here, I will utilize DREADD technology (designer receptors exclusively activated by designer drugs) to selectively drive neuronal activity in nDGCs. Specifically, I plan to generate and characterize a triple transgenic mouse line, NestinCreERT2:tdTomato:hM3Dq, and utilize the DREADD agonist, deschloroclozapine (DCZ), to stimulate nDGCs in PAE-EE mice. These aims are in accordance with the NIAAA’s mission to develop treatment strategies to address alcohol-related issues across the lifespan. This proposed research also serves as an important framework for training ...