This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Expression of adaptive stress-related behavior, and also of maladaptive stress and anxiety states, is strongly linked with the neurotransmitter serotonin (5HT) and the neurohormone corticotropin-releasing factor (CRF; Dunn and Berridge, 1990; Millan, 2003). Converging evidence suggests that 5HT cell body groups in the raphe nuclei play differential roles in the production of adaptive stress responses (Deakin, 1998; Lowry, 2002; Forster et al., 2004b). Infusions of CRF into the dorsal raphe nucleus (dRN) induces freezing behavior in rats (Forster et al., 2004b) ? an ecologically adaptive behavior expressed during, or in anticipation of, an aversive event (Fendt and Fanselow, 1999). Freezing behavior induced by CRF actions in the dRN may be a result of increased 5HT activity in the amygdala, since 5HT levels in the amygdala increases immediately during stress, and 5HT activity in this region is required for induction of freezing behavior (Macedo et al., 2002). In contrast, increased 5HT release in the medial prefrontal cortex (mPFC) is associated with cessation of CRF-elicited freezing behavior (Forster et al., 2004b). These increased mPFC 5HT levels following freezing behavior are actually derived from the median raphe (mRN), and may serve to limit stress responses adaptively (i.e. coping) (Forster et al., 2004b). These findings suggest a complex interplay is required between raphe nuclei and their terminal sites for production of adaptive behavioral responses and coping during stressful events. We hypothesize that during, or in anticipation of, an aversive event, CRF released into the dRN causes increased 5HT output to the amygdala, which facilitates expression of stress-related behavior, and also results in disinhibition of the mRN to allow increased mPFC 5HT activity to facilitate coping. Furthermore, we suggest that long-term alterations to this neural circuitry contribute to anxiety disorders by increasing stress responsiveness and reducing coping ability during the anticipation of aversive outcomes. Here we hypothesize that increased stress and anxiety behaviors as a result of social defeat in rats (a model of human socially induced anxiety) are a function of disruption to the balance between raphe 5HT systems and amygdala/mPFC 5HT activity, as regulated by CRF. Testing these hypotheses is central to the current COBRE themes, advancing our understanding of the neural circuitry underlying adaptive stress behavior and the development of maladaptive anxiety states.
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