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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。适应压力相关行为的表达，以及适应不良压力和焦虑状态，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和Berbridge，1990；Millan，2003)密切相关。越来越多的证据表明，中缝核内的5-羟色胺胞体群在产生适应性应激反应中发挥着不同的作用(Deakin，1998；Lowry，2002；Forster等，2004b)。将CRF注入中缝背核(DRN)诱导大鼠的冰冻行为(Forster等人，2004b)？在厌恶事件期间或预期中表现的生态适应性行为(Fendt和Fanselow，1999)。CRF在DRN中的作用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水平在应激期间立即增加，而该区域的5HT活动是诱导冻结行为所必需的(Macedo等人，2002年)。相反，内侧前额叶皮质(MPFC)增加的5-羟色胺释放与停止CRF诱导的冰冻行为有关(Forster等人，2004b)。这些在冰冻行为后升高的mPFC 5-HT水平实际上来自中缝中缝(MRN)，可能用于限制适应性的应激反应(即应对)(Forster等人，2004b)。这些发现表明，在应激事件中，中缝核团及其末端部位之间需要复杂的相互作用，以产生适应性行为反应和应对。我们假设，在厌恶事件期间或预期发生厌恶事件时，CRF释放到DRN会导致杏仁核5HT输出增加，这有助于应激相关行为的表达，也会导致MRN去抑制，从而允许mPFC 5HT活性增加，以促进应对。此外，我们认为，这种神经回路的长期变化通过增加压力反应和降低应对能力来导致焦虑症，在预期不良结果的过程中。在这里，我们假设，由于社交失败而导致的大鼠压力和焦虑行为的增加(人类社交诱导焦虑的模型)是受CRF调节的中缝5HT系统和杏仁核/mPFC 5HT活性之间平衡被破坏的函数。验证这些假说是当前Cobre主题的核心，有助于我们理解适应性应激行为和非适应性焦虑状态的发展背后的神经回路。