The overall goal of the proposed research is to characterize alterations in network connectivity of adult- generated dentate granule cells (aDGCs) in a mouse model of prenatal alcohol exposure (PAE). If successful, these studies may reveal mechanisms that underlie deficits in hippocampal function associated with fetal alcohol spectrum disorders (FASDs). The current proposal is designed to test the overall hypothesis that PAE disrupts experience-dependent remodeling of connectivity of newborn dentate granule neurons in the adult hippocampus. The proposal is premised on previous work demonstrating that exposure to even moderate levels of alcohol throughout gestation leads to an impaired neurogenic response to enriched environment and altered synaptic activity of aDGCs as assessed electrophysiologically. I will utilize a well-characterized limited access gestational exposure model in mice to characterize the impact of PAE on circuit connectivity of aDGCs. Specifically, I will utilize a combination of dual-vector tracing, high-resolution confocal imaging, electrophysiological and optogenetic approaches to address the following aims.
Specific Aim 1. To test the hypothesis that PAE disrupts EE-mediated remodeling of afferent synaptic input to aDGCs. Here we will assess the impact of PAE on the distribution of monosynaptic afferent input to aDGCs using a dual vector tracing system (Aim 1.1), morphological analysis of dendritic complexity and spine maturation in aDGCs (Aim 1.2), and functional synaptic input to aDGCs using whole-cell patch slice recordings of evoked synaptic activity (Aim 1.3).
Specific Aim 2. To test the hypothesis that PAE disrupts EE-mediated remodeling of efferent synaptic output from aDGCs. Here, I will assess the impact of PAE on excitatory efferent connections of aDGCs with CA3 pyramidal cells and interneurons using a neuroanatomical approach (Aim 2.1), coupled with optogenetic stimulation of aDGCs in hippocampal slice preparations (Aim 2.2).
These aims coincide with the mission of the NIAAA to attain fundamental knowledge for the improvement of alcohol-related problems, since understanding how PAE impacts hippocampal connectivity may reveal opportunities for novel circuitry-based therapeutic approaches to mitigate neurobehavioral consequences in clinical FASDs. Importantly, the proposed research provides a framework for research training in alcohol-related neuroscience utilizing state-of-the art approaches within an outstanding mentoring team and research environment within the New Mexico Alcohol Research Center.
Adult hippocampal neurogenesis is a unique form of brain plasticity important in certain forms of learning, memory and mood regulation; aspects of brain function that are dysregulated in FASDs. Here, we will utilize a well-characterized mouse model of PAE to investigate how gestational alcohol impacts network connectivity of adult-generated dentate granule cells. Determining fundamental alterations to hippocampal circuitry may lead to novel system-based targets for restoration of neurobehavioral deficits in FASD.
