Neural Basis of Spatial Memory Deficits After Prenatal Alcohol Exposure

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PROJECT SUMMARY/ABSTRACT Fetal Alcohol Spectrum Disorders are a set of major morphological, neurobiological, and cognitive abnormalities in offspring exposed to alcohol in utero. A common cognitive manifestation of alcohol exposure during neural development in humans, and in animal models of prenatal alcohol exposure (PAE), are deficits in spatial learning and memory. In moderate PAE, which accounts for the most common and underestimated form of PAE, spatial deficits are marked by an inability to accurately discriminate between spatial locations or recall previously learned spatial relationships. Systems-level monitoring of neural populations in the hippocampal formation has unraveled a critical role for this circuit in the generation of spatial memories and their subsequent recall. The well-characterized spatial and oscillatory organization of hippocampal spiking is thought to play a critical role in these processes. The long-term goal of our research program is to identify the neurobiological mechanisms of spatial learning and memory impairments after moderate PAE. While the behavioral phenotype of altered spatial behavior after moderate PAE is well established, there is still a critical need to identify the systems-level mechanisms including the neural circuitry and brain dynamics involved in such deficits. A multi-level understanding framework for the study of spatial impairments is essential in developing a complete understanding of the impact of PAE on nervous system function and toward the development of targeted interventions. The overall objective of this proposal is to identify these systems-level alterations by monitoring large ensembles of hippocampal neurons and their oscillatory dynamics during both spatial learning and memory and in “offline periods” of rest and sleep. In two aims, we will test our central hypothesis that PAE induced perturbations to spatial learning and memory are a consequence of a loss in the expression of distinct hippocampal ensemble codes for place and their synchronization and organization within hippocampal oscillations during rest and sleep. The aims of this R01 represent a critical step towards our long-term goal of identifying the neurobiological mechanisms of spatial learning and memory deficits after moderate PAE but will also provide critical insight into the systems-level impact of moderate PAE on hippocampal population activity. The relationship between hippocampal population activity and spatial learning and memory is well established in a wide range of species including humans. Thus, this proposal has the potential to provide a novel scientific framework whereby new strategies for interventions can be developed and tested in preclinical models but can also be developed for human patient populations.