McEwen and colleagues have recently found that granule neurons are replaced in the dentate gyrus (DG) of the adult brain and that this occurs not only in rodents but also in tree shrews and primates. Moreover, they found that acute and chronic stress inhibit neurogenesis in the DG. The amygdala exerts an important influence on excitability and long-term potentiation (LTP) in the DG, and both the amygdala and DG are targets for stress and contain receptors for stress hormones. The central hypothesis of Project 4 is that stressors facilitate mechanisms subserving fear in the arnygdala and inhibit neurogenesis in granule neurons of the DG, both acutely and chronically; moreover, chronic stress results in decreased DG volume and altered connectivity and function that impairs the ability of the hippocampus to participate in context-dependent fear. The sequence of studies is as follows. First, in collaboration with LeDoux (Project 1), amygdala and DG LTP will be explored, especially focusing on amygdala influences on DG LTP. Next, also with LeDoux (Project 1), we plan to investigate the effects of restraint stress and contextual fear conditioning on DG neurogenesis. Third, in collaboration with LeDoux (Project 1) and the Quantitative Morphology Core, the effects of repeated stress on DG neurogenesis and structure will be examined in relation to the amygdala and fear. Fourth, in collaboration with Morrison (Project 3), the effects of stress and glucocorticoid manipulations on the expression and distribution of NMDA and other excitatory amino acid receptors in the DG will be determined. Based upon the neurogenesis findings, we plan to determine if turnover of DG neurons affects stability of fear conditioning, again in collaboration with LeDoux (Project 1). Concurrently, with these studies, and based upon our initial results, we plan to assess changes in DG gene expression during contextual fear conditioning. Finally, in collaboration with Mony de Leon of NYU, and later in conjunction with Silbersweig, Stern, and Gorman (Project 2), we plan to investigate the anatomical basis of hippocampal atrophy in the human brain with MRI and eventually compare this with animal brain MRI, in particular, establishing and validating methods for measuring DG volume.
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