Influence of Chronic Stress on the Raphe Nucleus and Medial Prefrontal Cortex

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DESCRIPTION (provided by applicant): Serotonin, or 5-hydroxytryptamine (5-HT), is thought to regulate mood and contributes to stress-related, mood disorders such as anxiety and depression. Although much remains unknown about the pathophysiology of anxiety, the dorsal raphe (DR) and the medial prefrontal cortex (mPFC) are known to be particularly important. Previous studies have revealed anatomical and functional connectivity between the mPFC pyramidal cells, the DR GABA cells and the DR 5-HT cells, and the 5-HT1 A, 5-HT2A, and GABAA receptors are crucial mediators of the activity of cells within this circuit. Although each component of the DR-mPFC circuitry is thought to contribute to anxiety, few studies have precisely examined the way that these components are altered in a behavioral model of anxiety. Chronic social defeat is a potent stressor that produces many of the behavioral and physiological attributes seen in anxiety and related disorders. Some studies have examined the changes in neuronal activation and protein expression that occur as a result of chronic social defeat within the DR and mPFC. However, few of those studies specify the neurochemical identity of the analyzed cells or consider the subregional distribution of cells in their experimental design. The overall goal is to understand how chronic stress changes the way that subpopulations of cells in the DR and the mPFC modulate the function of the serotonin system. Tracing studies and immunohistochemistry will define the distribution of the subpopulation of DR cells that are interconnected with the mPFC. Whole-cell patch clamp electrophysiology will discern if this subpopulation exhibits distinct cellular characteristics and are differentially regulated in mice that experience chronic social defeat. The hypothesis is that social defeat selectively alters particular membrane properties and receptor-mediated responses within the DR-mPFC circuit to enhance negative feedback onto 5-HT cells. This line of experiments will contribute to an understanding of the cellular and molecular mechanisms that underlie anxiety and may one day highlight novel targets for drug development or help to refine existing methods of medical treatment. Anxiety and related disorders are thought to be mediated by changes in the serotonin system of the brain, but much remains unknown about what those changes are. The techniques used in this study allow for the measurment of changes in particular cells of the serotonin system to determine if they function differently in a mouse model of anxiety. By identifying components of the serotonin system that contribute to anxious behavior, this project may contribute to the development of novel drugs to treat human anxiety.