Neuroanatomy and molecular neurobiology of suicide

本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，由腹外侧前额叶皮层的缺陷介导，导致自杀行为。项目2A（腹侧前额叶皮层）有四个组成部分：(1)对自杀者和控制者的腹外侧和背侧前额叶皮层进行系统的细胞结构研究，以确定神经元密度。这可以作为一种指标，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的相关性，以及与脑干和皮层的受体密度测量的相关性；(2)候选基因与自杀和中枢血清素功能的关联研究（检测将由临床实验室核心完成）；(3)开发和应用微阵列技术，分析抑郁和非抑郁自杀者、抑郁和非抑郁非自杀者感兴趣的脑区基因表达（由临床实验室核心完成）；(4)在自杀受害者（抑郁和非抑郁）和正常对照中进行5-HT/2C受体前mrna编辑，然后在膜匀浆中使用5-HT/ 2A/2C受体激动剂促进35S-GTPgammaS的结合。2B项目拟开展一系列基因表达研究，包括5-羟色胺转运体、5-HT1A受体、色氨酸羟化酶和部分转录因子（如pCREB）在自杀者、抑郁症和非抑郁症对照者血清素能DRN中的表达。酗酒者是自杀的高危人群，2C项目建议通过免疫细胞化学和免疫放射自显影技术研究酗酒自杀者、酗酒非自杀者和对照者的血清素能神经元。提出的细胞结构学和分子生物学方法旨在确定四组脑干和皮层中可能的异常部位；自杀受害者，非精神病非自杀控制组，以及另外两个非自杀控制组：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.