Neurobiological studies of major depression have identified dysfunctional cognitive-affective-motor regions; however, the details of these altered physiological and structural changes, and the molecular basis for these alterations, remain to be elucidated. Recent imaging data suggest that depressed patients have increased blood flow/metabolism in the amygdala concomitant with decreased blood flow and volume in orbitofrontal cortex and ventromedial striatum. These effects may be relevant to the psychopathology of depression because cortico-limbic - striatal dysfunction may contribute to hypersensitive stress, fea4r, and anxiety responses, anhedonia, affective alterations, and changes in cognitive function. Thus, it is critical to understand the molecular basis of neuroplasticity in these brain regions implicated in depression and mood disorders and the resulting cellular and behavioral correlates. This project will thus focus on the role for the extended amygdala (notably the central nucleus of the amygdala, and nucleus accumbens shell) in depression and alterations in PKA/CREB signaling in these regions because the involvement of PKA/CREB in learning/plasticity is well established and because antidepressant treatment increases PKA/CREB activity. Specifically the functional and molecular correlates of plasticity in response to stress and antidepressant treatment will be investigated. We hypothesize that alterations in the extended amygdala results in abnormal processing of affective/emotional stimuli and behavioral regulation by appetitive and aversive events. Combined with alterations of neural signaling within the ventral striatum that contribute to anhedonia, negative stimuli may also exert heightened suppressive consequences on behavior in depression. In addition, sustained increases PKA/CREB produced by anti-depressants would be predicted modify behavior by enhancing plasticity associated with learning and affective processes. Using direct pharmacological manipulations, transgenic murine models, vector-mediated over-expression of CREB and stress-induced animal models of depression, we will investigate the role of PKA/CREB signaling within the extended amygdala in reactivity to unconditioned aversive stimuli and/or anhedonia (sensitivity to appetitive rewards), and appropriate control procedures, as well as the mechanism of action of anti-depressant drugs in order to evaluate and validate the relevance of these processes to models of depression.
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