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: 7959608
• 负责人: Gina L Forster
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959608
• 关键词: Adaptive Behaviors; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Centers of Research Excellence; Complex; Computer Retrieval of Information on Scientific Projects Database; Corticotropin-Releasing Hormone; Development; Disinhibition; Equilibrium; Event; Freezing; Funding; Grant; Human; Infusion procedures; Institution; Link; Medial; Modeling; Neurohormones; Neurotransmitters; Outcome; Output; Play; Prefrontal Cortex; Production; Rattus; Research; Research Personnel; Resources; Role; Serotonin; Site; Source; Stress; Stressful Event; System; Testing; United States National Institutes of Health; biological adaptation to stress; coping; dorsal raphe nucleus; neural circuit; neuromechanism; neuronal cell body; raphe nuclei; response; social

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 适应性压力相关行为以及适应不良压力和焦虑状态的表达与神经递质血清素（5HT）和神经激素促肾上腺皮质激素释放因子密切相关（CRF；Dunn 和 Berridge，1990；Millan，2003）。 综合证据表明，中缝核中的 5HT 细胞体群在适应性应激反应的产生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) 会诱导大鼠出现冻结行为（Forster 等人，2004b）？在厌恶事件期间或预期发生厌恶事件时表现出的生态适应性行为（Fendt 和 Fanselow，1999）。 dRN 中 CRF 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，并且该区域的 5HT 活性是诱导冻结行为所必需的（Macedo 等，2015）。 ，2002）。 相反，内侧前额皮质 (mPFC) 中 5HT 释放的增加与 CRF 引起的冻结行为的停止相关（Forster 等，2004b）。 冻结行为后 mPFC 5HT 水平的增加实际上源自中缝 (mRN)，并且可能有助于适应性地限制应激反应（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应激事件。 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 会导致杏仁核的 5HT 输出增加，从而促进压力相关行为的表达，并且还会导致 mRN 去抑制，从而增加 mPFC 5HT 活性以方便应对。 此外，我们认为这种神经回路的长期改变会增加压力反应性并降低预期厌恶结果期间的应对能力，从而导致焦虑症。 在这里，我们假设大鼠（人类社交诱发焦虑的模型）因社交失败而增加的压力和焦虑行为是中缝 5HT 系统和杏仁核/mPFC 5HT 活性之间平衡被破坏的结果，由 CRF 调节。 测试这些假设是当前 COBRE 主题的核心，它增进了我们对适应性压力行为背后的神经回路和适应不良焦虑状态发展的理解。