Neuroanatomy and molecular neurobiology of suicide

自杀的神经解剖学和分子神经生物学

• 批准号: 6643681
• 负责人: Victoria Arango
• 金额: $ 17.72万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643681
• 关键词: alcoholism /alcohol abuse; autoradiography; behavioral /social science research tag; behavioral genetics; brain mapping; clinical depression; clinical research; gene expression; genetic mapping; human subject; human tissue; immunocytochemistry; microarray technology; neurochemistry; postmortem; serotonin receptor; serotonin transporter; suicide; transcription factor; tryptophan 5 monooxygenase

This project aims to utilize the unique resources of the Human Neurobiology Core Brain Bank to investigate further our hypothesis of behavior disinhibition, mediated by deficits in the ventrolateral prefrontal cortex, that lead to suicidal behavior. Project 2A (Ventral Prefrontal Cortex) has four components: (1) systematic cytoarchitectonic investigation of ventrolateral and dorsal prefrontal cortex of suicides and controls, to determine neuron density. This serves as an index to be able to obtain correlations with the numbers of brainstem serotonergic and noradrenergic source neurons, as well as with receptor density measures in the brainstem and cortex; (2) Association studies of candidate genes with suicide and central serotonin function (Assays will be done by the Clinical Laboratory Core); (3) Development and application of microarray technology to analyze gene expression in brain areas of interest of depressed and non-depressed suicides, depressed and non- depressed non-suicides (Assays will be done by the Clinical Laboratory Core); and (4) 5-HT/2C receptor pre-mRNA editing in suicide victims (depressed and non-depressed) and normal controls, followed by 5- HT/2A/2C receptor agonist-promoted binding of 35S-GTPgammaS in membrane homogenates. Project 2B proposes a series of gene expression studies in the serotonergic DRN of suicide victims and depressed and non-depressed controls, including the serotonin transporter, 5-HT1A receptor, tryptophan hydroxylase and select transcription factors (e.g. pCREB). Alcoholics represent a high-risk population for suicide and Project 2C proposes to study the serotonergic neurons of alcoholic suicides, alcoholic non-suicides and controls by immunocytochemistry and immunoautoradiography. The proposed cytoarchitectonic and molecular biological approaches aim to identify possible sites of abnormality in the brainstem and cortex of four groups; suicide victims, non-psychiatric non-suicide controls, and two other non-suicide control groups: depressed and alcoholics.

该项目旨在利用人类神经生物学核心脑库的独特资源，进一步研究我们的行为去抑制假设，该行为抑制是由腹外侧前额叶皮层缺陷介导的，从而导致自杀行为。项目 2A（腹侧前额叶皮质）有四个组成部分：（1）对自杀者和对照组的腹外侧和背侧前额叶皮质进行系统的细胞结构研究，以确定神经元密度。这是能够获得与脑干血清素能和去甲肾上腺素能源神经元数量以及脑干和皮质中受体密度测量的相关性的指标； (2) 候选基因与自杀和中枢血清素功能的关联研究（由临床实验室核心进行检测）； (3) 开发和应用微阵列技术来分析抑郁症和非抑郁症自杀者、抑郁症和非抑郁症非自杀者感兴趣的大脑区域的基因表达（检测将由临床实验室核心完成）； (4)自杀受害者(抑郁和非抑郁)和正常对照中的5-HT/2C受体前体mRNA编辑，随后5-HT/2A/2C受体激动剂促进膜匀浆中35S-GTPgammaS的结合。项目 2B 提议对自杀受害者以及抑郁和非抑郁对照组的血清素 DRN 进行一系列基因表达研究，包括血清素转运蛋白、5-HT1A 受体、色氨酸羟化酶和选择的转录因子（例如 pCREB）。酗酒者是自杀的高危人群，2C 项目提议通过免疫细胞化学和免疫放射自显影技术研究酒精自杀者、酒精非自杀者和对照组的血清素能神经元。所提出的细胞结构和分子生物学方法旨在识别四组脑干和皮质中可能的异常部位；自杀受害者、非精神病非自杀对照组以及另外两个非自杀对照组：抑郁症患者和酗酒者。