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: 7162078
• 负责人: HEIDI E DAY
• 金额: $ 28.39万
• 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: 2005-01-08 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162078
• 关键词: Amphetamines; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Brain; Brain region; Butyric Acid; Butyric Acids; Cell Nucleus; Cells; Central Medial Thalamic Nucleus; Cholera Toxin Protomer B; Condition; Corticosterone; Corticotropin-Releasing Hormone; Disease; Disinhibition; Endocrine; Enkephalins; Environment; Etiology; Exposure to; FOS gene; Fright; Gene Expression; Gene Expression Regulation; Genes; Glutamate Decarboxylase; Glutamates; Goals; Heterogeneous Nuclear RNA; Immediate-Early Genes; Immunohistochemistry; In Situ Hybridization; Injection of therapeutic agent; Knowledge; Lateral; Lead; Lesion; Measures; Medial; Mediating; Medical; Mental disorders; Messenger RNA; Microdialysis; Microinjections; Mood Disorders; Neurons; Noise; Numbers; Output; Phaseolus vulgaris leucoagglutinin; Phenotype; Process; Protein Isoforms; Psychological Stress; Range; Role; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Substance P; System; Testing; Thinking; Time; Work; base; day; design; gamma-Aminobutyric Acid; in vivo; mRNA Expression; neural circuit; neurochemistry; novel; parabrachial nucleus; programs; psychological stressor; receptor; relating to nervous system; research study; response; restraint; restraint stress; stressor; vesicular glutamate transporter 1

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，心理压力可以加速或加剧许多医疗条件，包括精神疾病。一个被认为对压力、恐惧和焦虑反应非常重要的大脑系统是中央延伸杏仁核。这个建议是基于这样一个假设，即杏仁核的主要输出核（中央核，CEA）和相关的脑区，终纹床核（BST）通常如何响应心理压力的知识将最终帮助我们理解一些受压力影响的疾病的病因。由于在恐惧和焦虑行为中所表现出的作用，先前已经针对CEA的激活进行了大量的努力。然而，最近的研究表明，暴露于新奇的心理压力，巨大的噪音或约束导致安非他明诱导的c-fos mRNA表达减少（约50%），在BST（BSTov）和CEA（CEAI）的外侧分裂的卵圆核含enkaphalin的神经元，这表明心理压力实际上抑制了这些大脑区域。潜在地，对这些也是GABA能的神经元的抑制将导致对它们的传出靶的去抑制。这些靶点包括BST的梭状核、臂旁外侧核和内侧CEA，它们共同调节因压力和焦虑而改变的几种自主神经、内分泌和行为反应。本申请中描述的实验被设计为进一步表征心理应激对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中作为暴露于心理应激的直接结果而发生的基因表达的潜在变化（立即早期基因、脑啡肽、CRH、P物质或谷氨酸脱羧酶65和67）。这些变化可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这些区域中的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）与含脑啡肽的细胞。目的2中的实验被设计为评估涉及心理应激对BSTov和CEA的影响的神经回路。逆行和顺行追踪，双重免疫组织化学，神经化学病变和谷氨酸注射的组合将被用来确定是否有至少一个脑区，项目的CEAI和BSTov，这是激活的压力，这是必要的和足够的压力诱导的基因表达变化在这些脑区。GABA（γ-氨基丁酸）在这些应激诱导的变化中的潜在作用也将通过确定GABA能输入BSTov和CEAI、应激期间GABA的体内微透析以及在应激暴露之前将GABAA和GABAC受体拮抗剂颅内注射到BSTov和CEA中来评估。最后，人们希望了解压力下通常参与的基本神经回路，可能有助于确定某些精神疾病病因中涉及的一些神经过程。