Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure

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PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to establish the relevance of adult hippocampal neurogenesis as a potential therapeutic target for fetal alcohol spectrum disorder (FASD), utilizing a well-characterized mouse model of prenatal alcohol exposure (PAE). The significance for adult hippocampal neurogenesis as a potential therapeutic target in fetal alcohol spectrum disorder (FASD) is based on preclinical rodent models that demonstrate long- lasting deficits in neurogenesis following developmental alcohol exposure, the critical role of neurogenesis in many hippocampal-dependent behaviors that are also disrupted in clinical FASD, and recent evidence that neurogenesis continues throughout life in the human hippocampus. Using voluntary drinking paradigms to model PAE in mice, our laboratory previously demonstrated marked impairment of the neurogenic response to enriched environment (EE) that is associated with disruption of neurochemical, morphological and electrophysiological indices of EE-mediated network activity. Experiments outlined in this proposal are designed to test the overall hypothesis that impaired EE-mediated neurogenesis is relevant for deficits in behavior and hippocampal network mechanisms in PAE, and can be restored using genetic and/or pharmacological therapeutic approaches. This hypothesis will be tested by addressing the following specific aims. Specific Aim 1: To determine whether impaired EE-mediated neurogenesis is directly correlated with impaired pattern discrimination learning in PAE mice. We will utilize two complex neurogenesis-dependent cognitive tasks in which pattern discrimination/separation is tested in both contextual and spatial domains. Behavioral performance will be correlated with impaired neurogenesis in PAE-EE mice, and with immediate early gene expression as a readout of network activation. Specific Aim 2: To determine whether impaired EE-mediated neurogenesis in PAE mice leads to compensatory remodeling of afferent synaptic input to aDGCs. We will utilize neuroanatomical approaches including rabies-based retrograde tracing to determine whether dendritic complexity and/or the distribution of monosynaptic afferent inputs to aDGCs are selectively altered in PAE-EE mice. Specific Aim 3: To determine whether sensitivity to EE-mediated neurogenesis in PAE mice is restored by genetic and/or pharmacological intervention. We will utilize a genetic gain-of-function approach to augment the survival of aDGCs in an attempt to restore EE-mediated neurogenesis in PAE mice. In addition, we will test whether the neurogenic antidepressant, fluoxetine (FLX), restores EE-mediated neurogenesis and behavior in PAE. If so, causal relationships between neurogenesis and FLX-mediated behavioral improvement will be tested by selective, genetic silencing of aDGCs.