NEURAL MECHANISMS UNDERLYING ADAPTIVE COPING SOCIALLY INDUCED ANXIETY

适应性应对社会引起的焦虑的神经机制

• 批准号: 7381105
• 负责人: Gina L Forster
• 金额: $ 12.05万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381105
• 关键词: NEURAL; MECHANISMS; UNDERLYING; ADAPTIVE; COPING

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。适应性应激相关行为的表达，以及适应不良应激和焦虑状态的表达，与神经递质5-羟色胺（5-HT）和神经激素促肾上腺皮质激素释放因子密切相关（CRF; Dunn and Berridge，1990; Millan，2003）。越来越多的证据表明，中缝核中的5 HT细胞体群在适应性应激反应的产生中起着不同的作用（Deakin，1998; Lowry，2002; Forster et al.，2004年b）。将CRF输注到中缝背核（dRN）中诱导大鼠的冻结行为（Forster等人，2004年b）？在一个令人厌恶的事件中或预期中表现出的一种生态适应行为（Fendt和Fanselow，1999）。dRN中由CRF作用诱导的冻结行为可能是杏仁核中5 HT活性增加的结果，因为杏仁核中的5 HT水平在应激期间立即增加，并且该区域中的5 HT活性是诱导冻结行为所需的（Macedo et al.，2002年）。相反，内侧前额叶皮层（mPFC）中5 HT释放的增加与CRF引起的冻结行为的停止有关（Forster et al.，2004年b）。这些增加的mPFC 5 HT水平后冻结行为实际上是来自中缝（mRN），并可能有助于限制压力反应适应性（即应对）（福斯特等人，2004年b）。这些发现表明，中缝核团和它们的终端站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，在过程中，或在预期中，一个令人厌恶的事件，CRF释放到dRN的原因增加5 HT输出到杏仁核，这有利于表达的压力相关的行为，也导致解除抑制的mRN允许增加mPFC 5 HT活性，以促进应对。此外，我们认为，这种神经回路的长期改变有助于焦虑症的增加压力反应和减少应对能力在预期的厌恶结果。在这里，我们假设，增加压力和焦虑行为的结果，在大鼠的社会失败（人类社会诱导的焦虑模型）是一个功能的破坏中缝5 HT系统和杏仁核/mPFC 5 HT活性之间的平衡，调节CRF。测试这些假设是当前COBRE主题的核心，推进了我们对适应性压力行为和适应不良焦虑状态发展背后的神经回路的理解。