NEURAL MECHANISMS UNDERLYING ADAPTIVE COPING SOCIALLY INDUCED ANXIETY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。适应性压力相关行为的表达，以及适应不良的压力和焦虑状态，与神经递质5 -羟色胺（5HT）和神经激素促肾上腺皮质激素释放因子（CRF; Dunn and Berridge, 1990; Millan, 2003）密切相关。越来越多的证据表明，中缘核中的5HT细胞体群在产生适应性应激反应中起着不同的作用（Deakin, 1998; Lowry, 2002; Forster et al., 2004b）。向中缝背核（dRN）注入CRF可诱导大鼠冻结行为（Forster et al., 2004b）。在厌恶事件期间或预期中表达的生态适应性行为（Fendt和Fanselow， 1999）。CRF作用在dRN中诱导的冻结行为可能是杏仁核中5HT活性增加的结果，因为杏仁核中的5HT水平在应激时立即增加，而该区域的5HT活性是诱导冻结行为所必需的（Macedo等人，2002）。相反，内侧前额叶皮层（mPFC）中5HT释放的增加与crf引起的冻结行为的停止有关（Forster等，2004b）。冻结行为后mPFC - 5HT水平的增加实际上来自中位数中线（mRN），可能有助于自适应地限制应激反应（即应对）（Forster等人，2004b）。这些发现表明，中缝核与其末端位点之间需要复杂的相互作用，以产生适应性行为反应和应对压力事件。我们假设，在厌恶事件发生期间或预期发生时，释放到dRN的CRF会导致杏仁核5HT输出增加，从而促进应激相关行为的表达，同时也会导致mRN的去抑制，从而增加mPFC 5HT活性，以促进应对。此外，我们认为这种神经回路的长期改变会增加应激反应，并在预期不良结果时降低应对能力，从而导致焦虑症。在这里，我们假设，由于大鼠的社会失败（人类社会诱导焦虑的一种模型），压力和焦虑行为的增加是中脑5HT系统和杏仁核/mPFC 5HT活性之间的平衡被破坏的功能，由CRF调节。测试这些假设是当前COBRE主题的核心，促进了我们对适应性应激行为和适应不良焦虑状态发展的神经回路的理解。

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.