Benjamin J. Clark, Ph.D. - US grants

PROJECT SUMMARY Fetal Alcohol Spectrum Disorders (FASD) are a major public health problem with an incidence of 1-5% in the USA and associated annual costs in excess of $4 billion. The majority of FASD cases fall within the less severe range of the spectrum, characterized by behavioral and cognitive deficits in the absence of conspicuous alterations in craniofacial or brain morphology. Memory deficits are among the more profound lifelong, negative effects on exposure to alcohol during prenatal brain development. At present there are no treatments for memory deficits associated with FASD. Lack of knowledge regarding how prenatal alcohol exposure (PAE) alters brain functions critical for memory represents a major barrier to progress on efforts to identify and develop potential treatments. Moderate PAE in rat models of less severe FASD leads to impairments in spatial memory that persist throughout adulthood. The proposed research will test an innovative and novel hypothesis regarding the neural bases of moderate PAE effects on spatial memory. Place cells in the hippocampus increase in activity selectively when an animal occupies a particular spatial location. The population code provided by place cells represents a spatial ?map?. In healthy animals these spatial maps tend to remain stable for months, however, reduced stability in place cells has been linked to spatial memory impairments. Instability in the neural representations of spatial memory may, thus, represent a systems level mechanism for spatial memory impairments observed following PAE. The proposed research will test the hypothesis that PAE reduces place cell stability, and that reductions in place cell stability are predictive of spatial memory impairments following PAE. In the proposed studies adult rats exposed to moderate levels of ethanol during gestational developmental will be implanted with electrodes in the dorsal hippocampus and the stability of hippocampal place cells will be quantified over multiple sessions. If PAE reduces place cell stability, then the pattern of spatially-selective firing of these cells will be more likely to change (?remap?) from session to session. We will examine whether instability in hippocampal place cells of rats exposed to alcohol is predictive of impaired spatial memory in the Morris water task and in a plus-maze task. Significance and Innovation : The proposed research will be the first study to examine the effects of PAE on neural representations of spatial information and the relationship to spatial memory deficits. This project will serve as a foundation for future studies on mechanisms and treatments. Establishing the utility of this model systems approach is important because it could facilitate identification of putative mechanisms underlying PAE-related spatial memory deficits at circuit, network, receptor, and molecular levels of analysis, which could help identify and evaluate treatment strategies. Because spatial memory deficits are observed in children with FASD, studying the neurobiology of spatial memory in rodent models of FASD could also hold considerable translational significance.