HUMAN POSTMORTEM STUDIES OF THE STRESS AXIS

人体死后压力轴研究

• 批准号: 6302590
• 负责人: STANLEY J WATSON
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302590
• 关键词: antidepressants; behavioral /social science research tag; brain; brain mapping; computer simulation; corticosteroid receptors; drug interactions; gene expression; high performance liquid chromatography; human tissue; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; molecular pathology; mood disorders; neuroanatomy; norepinephrine; pituitary adrenal axis; postmortem; psychological stressor; receptor binding; serotonin; statistics /biometry; suicide

Studying the neuroanatomical substrates of stress, suicide and depression in human brain is the central theme of this project. While these are also major foci of this entire Program Project application, this project specifically emphasizes postmortem human brain in an effort to understand the fundamental anatomy of stress-related circuits in man, and the possible changes in gene expression within these circuits which may accompany suicide and depression; in addition, however, this project includes some pre-clinical studies in the rodent specifically focused on the interface between stress circuits and the sites of action of antidepressant drugs, as these studies will help us interpret the human findings. Therefore, this project comprises 3 Specific Aims. The first Specific Aim involves the study of serotonergic (5HT) and nor-adrenergic (NA) systems as they respond to stress and antidepressants in rodent models. These paradigms will allow us to establish a clearer view of the functional links between the stress axis and monoamine systems, thereby clarifying the impact of monoamine-altering compounds on depression and on the endocrine disturbances associated with it. The second Specific Aim directly analyzes postmortem human brain from suicide victims, suicide victims also having a documented history of affective disease, and controls. The same circuits and systems laid out in the rodent will now be analyzed inhuman brain (prefrontal cortex, limbic circuits associated with the stress axis, 5HT and NA nuclei and their receptors). The third Specific Aim is designed to allow the three-dimensional (3D) analysis of individual human brain nuclei at cellular resolution using mRNA levels. This method will substantially increase the power and value of human postmortem studies by combining the regulatory information found in mRNA levels with anatomical precision and with high resolution statistical tools. In sum, at the end of the requested 5 years of this proposal we expect that we will have made very substantial gains in appreciating the circuitry of the stress axis in rodent and man, and begun to establish the relationship between the stress axis and affective disease at the level of biochemically specific brain nuclei and structures.

研究压力、自杀和抑郁症的神经解剖学基础 人脑抑郁症是该项目的中心主题。 尽管 这些也是整个计划项目申请的主要焦点， 该项目特别强调死后人类大脑的努力 了解人类压力相关回路的基本解剖结构， 以及这些回路中基因表达可能发生的变化 可能伴随自杀和抑郁；然而此外，这个项目 包括一些专门针对啮齿类动物的临床前研究 在压力回路和作用位点之间的界面上 抗抑郁药物，因为这些研究将帮助我们解释人类 发现。 因此，该项目包括 3 个具体目标。 第一具体 目标涉及血清素能 (5HT) 和去甲肾上腺素能 (NA) 的研究 啮齿动物模型中的系统对压力和抗抑郁药物的反应。 这些范式将使我们能够对 应力轴和单胺系统之间的功能联系，从而 阐明单胺改变化合物对抑郁症的影响 与此相关的内分泌紊乱。 第二具体 Aim 直接分析自杀受害者死后的大脑， 自杀受害者也有情感疾病病史， 和控制。 啮齿动物体内的相同电路和系统将 现在在人脑中进行分析（前额皮质、边缘回路 与应力轴、5HT 和 NA 核及其受体相关）。 第三个具体目标旨在允许三维 (3D) 使用细胞分辨率分析单个人脑核 mRNA 水平。 这种方法将大大提高功率和 结合监管部门的人体尸检研究的价值 在 mRNA 水平中发现的信息具有解剖精度和高 分辨率统计工具。 总而言之，在所要求的 5 结束时 经过多年的努力，我们预计我们将取得非常实质性的成果 在了解啮齿类动物的应激轴回路方面取得的进展 人，并开始建立应力轴和 生化特异性脑核水平的情感疾病 和结构。