Neuroanatomy and molecular neurobiology of suicide

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说，即由腹外侧额叶皮质缺陷介导的导致自杀行为的行为去抑制。项目2A(腹侧前额叶皮质)包括四个部分：(1)对自杀者和对照组腹外侧额叶皮质和背侧前额叶皮质进行系统的细胞构筑研究，以确定神经元密度。这是一个指数，能够获得与脑干5-羟色胺和去甲肾上腺素能源神经元的数量以及脑干和皮质中的受体密度测量的相关性；(2)候选基因与自杀和中枢5-羟色胺功能的关联研究(分析将由临床实验室核心完成)；(3)微阵列技术的开发和应用，以分析抑郁和非抑郁自杀、抑郁和非抑郁非自杀的大脑感兴趣区域的基因表达(分析将由临床实验室核心完成)；(4)在自杀者(抑郁症和非抑郁症)和正常对照组中编辑5-HT/2C受体前mRNA，然后用5-HT/2A/2C受体激动剂促进膜匀浆中35S-GTP-Gamma的结合。2B项目建议对自杀者、抑郁症和非抑郁症对照组的5-羟色胺能DRN进行一系列基因表达研究，包括5-羟色胺转运体、5-HT1a受体、色氨酸羟基酶和选定的转录因子(例如pCREB)。酗酒者是自杀的高危人群，项目2C建议通过免疫细胞化学和免疫放射自显影来研究酒精自杀者、酒精非自杀者和对照组的5-羟色胺能神经元。拟议的细胞结构和分子生物学方法旨在确定四个组的脑干和皮质可能的异常部位：自杀受害者、非精神病非自杀对照组和另外两个非自杀对照组：抑郁症和酗酒者。

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.