The Role of the Central Amygdala and BST in Stress

中央杏仁核和 BST 在压力中的作用

• 批准号: 6867894
• 负责人: HEIDI E DAY
• 金额: $ 28.99万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867894
• 关键词: amygdala; behavioral /social science research tag; corticotropin releasing factor; enkephalins; gamma aminobutyrate; gene expression; glutamate decarboxylase; immunocytochemistry; in situ hybridization; laboratory rat; microdialysis; neuroregulation; physiologic stressor; psychological stressor; radioimmunoassay; regulatory gene; stimulus /response; substance P; thalamus

DESCRIPTION (provided by applicant): A wealth of evidence has suggested that psychological stress can precipitate or exacerbate many medical conditions, including psychiatric illnesses. One brain system that is thought to be very important for responses to stress, fear and anxiety is the central extended amygdala. This proposal is based on the assumption that knowledge of how a major output nucleus of the amygdala (the central nucleus, CEA) and a related brain region, the bed nucleus of the stria terminalis (BST) normally responds to psychological stress will ultimately help us to understand the etiology of some disorders influenced by stress. Because of the demonstrated role in fear and anxiety behaviors, a significant effort has previously been directed at demonstrating activation of the CEA. However, it has recently been shown that exposure to the psychological stress of novelty, loud noise or restraint results in a decrease (~50 percent) in amphetamine-induced c-fos mRNA expression in enkaphalin-containing neurons of the oval nucleus of the BST (BSTov) and lateral division of the CEA (CEAI), suggesting that psychological stress in fact inhibits these brain regions. Potentially, inhibition of these neurons, that are also GABAergic, would result in disinhibition of their efferent targets. These targets include the fusiform nucleus of the BST, the lateral parabrachial nucleus, and the medial CEA that collectively regulate several autonomic, endocrine, and behavioral responses that are altered by stress and anxiety. The experiments described in this application are designed to further characterize the effects of psychological stress on the BSTov and CEA. In Aim 1, potential changes in gene expression (immediate early genes, enkephalin, CRH, substance P or glutamic acid decarboxylase 65 and 67) that occur in the BSTov and CEA as a direct result of exposure to psychological stress will be assessed by semi-quantitative in situ hybridization. These changes could be used as an alternative independent measure in subsequent experiments. In addition, it will be determined if stress inhibition of the BSTov and CEAI generalizes to conditioned versus unconditioned stress and to corticotropin releasing hormone- (CRH) versus enkephalin-containing cells in these regions. Experiments in Aim 2 are designed to assess the neural circuitry involved in psychological stress effects on the BSTov and CEA. A combination of retrograde and anterograde tracing, dual immunohistochemistry, neurochemical lesions and glutamate injections will be used to determine if there is at least one brain region that projects to both the CEAI and the BSTov, that is activated by stress, and that is necessary and sufficient for the stress-induced gene expression changes in these brain regions. The potential role of GABA (y-amino butyric acid) in these stress-induced changes will also be assessed by determination of GABAergic inputs to the BSTov and CEAI, in vivo microdialysis for GABA during stress, and intracranial injection of GABAA and GABAC receptor antagonists into the BSTov and CEA prior to stress exposure. Ultimately, it is hoped that knowledge of the basic neural circuitry normally engaged following exposure to stress might help to identify some of the neural processes involved in the etiology of some psychiatric disorders.

描述（由申请人提供）：大量证据表明，心理压力会引发或加剧许多健康状况，包括精神疾病。中央延伸杏仁核被认为对于应对压力、恐惧和焦虑非常重要，这是一种大脑系统。该提议基于这样的假设：了解杏仁核的主要输出核（中央核，CEA）和相关的大脑区域，终纹床核（BST）通常如何对心理压力做出反应，将最终帮助我们了解一些受压力影响的疾病的病因。由于 CEA 在恐惧和焦虑行为中的作用已被证实，因此之前已经做出了大量努力来证明 CEA 的激活。然而，最近的研究表明，暴露于新奇、大声噪音或束缚等心理压力会导致 BST (BSTov) 和 CEA (CEAI) 卵圆核 (BSTov) 和 CEA 侧裂 (CEAI) 卵圆核 (CEAI) 卵圆核内含脑啡肽神经元中苯丙胺诱导的 c-fos mRNA 表达下降 (约 50%)，这表明心理压力实际上抑制了这些大脑区域。抑制这些同样具有 GABA 能的神经元可能会导致其传出靶点的去抑制。这些目标包括 BST 的梭状核、外侧臂旁核和内侧 CEA，它们共同调节因压力和焦虑而改变的多种自主、内分泌和行为反应。本申请中描述的实验旨在进一步表征心理压力对 BSTov 和 CEA 的影响。在目标 1 中，将通过半定量原位杂交评估 BSTov 和 CEA 中由于暴露于心理压力而直接导致的基因表达（立即早期基因、脑啡肽、CRH、P 物质或谷氨酸脱羧酶 65 和 67）的潜在变化。这些变化可以在后续实验中用作替代的独立测量。此外，还将确定 BSTov 和 CEAI 的应激抑制是否普遍适用于条件应激与非条件应激，以及促肾上腺皮质激素释放激素 (CRH) 与这些区域中的含脑啡肽细胞。目标 2 中的实验旨在评估心理压力对 BSTov 和 CEA 影响所涉及的神经回路。逆行和顺行追踪、双重免疫组织化学、神经化学损伤和谷氨酸注射的组合将用于确定是否存在至少一个投射到CEAI和BSTov的大脑区域，该区域被压力激活，并且对于这些大脑区域中压力诱导的基因表达变化是必要和充分的。 GABA（γ-氨基丁酸）在这些应激引起的变化中的潜在作用也将通过测定 BSTov 和 CEAI 的 GABAergic 输入、应激期间 GABA 的体内微透析以及应激暴露前向 BSTov 和 CEA 颅内注射 GABAA 和 GABAC 受体拮抗剂来评估。最终，人们希望了解压力后通常参与的基本神经回路的知识可能有助于识别与某些精神疾病的病因学有关的一些神经过程。