This revised application seeks support for the Emory Center for the Neuroscience of Mental Disorders (ECNMD) in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine. The major goal of this five year research plan is to characterize the persistent neurobiological consequences of adverse events early in life and to determine the relationship of such long-lived central nervous system (CNS) alterations to the development of affective disorders, particularly depression, in adulthood. Two animal models of early adverse experience, for which pilot data on persistent neurobiological alterations exist, will comprise the bulk of the proposed work. These two models include a particularly well documented rodent model of maternal separation and a non-human primate variable foraging demand model of early stress. Gender-specific effects of early life stress will also be evaluated in these models. All of the preclinical projects will receive CNS tissue and biological fluids from each of these animal models. Neural circuits that have been implicated in both the neurobiology of stress and anxiety as well as the neurobiology of depression-like syndrome will be scrutinized, including corticotropin-releasing factor (Proj l; PI: Plotsky), serotonin (Proj 2; PLC Owens), dopamine and norepinephrine (Proj 3; PI: Kuhar), and signal transduction systems (Proj 4; PI: Nestler), hippocampal neurogenesis and remodeling (Proj 5; PI: Gould) and acoustic startle plasticity (Proj 6; PI: Davis) will be characterized in these models. In addition two clinical research projects will be included. Project 7, conducted both at Emory University (PI: Nemeroff) and Yale University (PI: Bremner), will examine the neurobiological consequences of child abuse by studying women with a past history of child abuse who are currently suffering from an episode of major depression versus a group of women who are currently depressed without a history of child abuse and a group of women with a history of child abuse without major depression. Finally, Project 8 will seek to determine the neurobiological and behavioral consequences of maternal depression during pregnancy or in the postpartum period on their children (PI: S.Goodman, Stowe). These research projects will be supported by an administrative core led by the Center Director, a rodent animal core (PI: Plotsky, Weiss), a primate animal core (PI: Insel, Winslow), an assay core (PI: Bonsall, Ritchie), and an integrated functional brain imaging core (PI: M. Goodman, Kilts). We postulate a model in which genetic vulnerability coupled with early trauma in a critical plastic period of development results in sensitization of neural systems which when exposed to even mild stressors in adulthood responds in a heightened manner, resulting in the neurobiological alterations that underlie the syndrome of depression. These studies have important implications not only for the neurobiology of depression but the development of novel treatment strategies for both depression and child abuse.
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