NEUROBIOLOGICAL BRAIN ABNORMALITIES IN DEPRESSIVE ILLNESS

抑郁症中的神经生物学大脑异常

• 批准号: 6231103
• 负责人: William E BUNNEY
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6231103
• 关键词: bipolar depression; brain mapping; cingulate gyrus; clinical research; complementary DNA; developmental genetics; developmental neurobiology; disease /disorder etiology; gene expression; genetic markers; human tissue; in situ hybridization; major depression; messenger RNA; neurogenetics; neuropathology; postmortem; prefrontal lobe /cortex; schizophrenia; thalamic nuclei

This Center project focuses on the issue as to whether patterns of gene expression are differentially changed in depressed versus control brain tissue and whether this information can be used to define dysregulations of circuitry which involve the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate gyrus and the mediodorsal (MD) thalamic nuclei. The hypothesis to be explored is that there is a disruption in the associative circuitry involving these structures is neurodevelopmentally based and more sensitive to epigenetic stresses that are documented to precede the initial onset of depression. A body of emerging data shows that a subgroup of depressed patients have increased ventricular size, hypofrontality plus other neuropathological findings similar to those that led to the neurodevelopmental hypothesis of schizophrenia. Missing is direct neuropathological evidence such as that found in schizophrenia. We reported that three neuronal markers of the embryonic cortical subplate quantified in postmortem tissue from schizophrenic brains are abnormally distributed relative to matched normal controls and our recent data implicates the thalamus as well. The cortical subplates, formed during the second most direct data for a neurodevelopmental hypothesis of schizophrenia can be interpreted as a defect of neuronal migration or of programmed cell death in the subplate. A positive neuropathological finding could represent an important first step would support a neurodevelopmental hypothesis of depression and will point to a potentially productive focus on specific brain regions and molecules to be investigated in association with microarray analyses. A unique group of brains from depressed and control subjects have been collected, evaluated clinically by history, matched for age, gender and autolysis time and prepared for analysis by a novel method recently developed. Specific research aims include 1) Quantify and assess the morphology of interstitial neurons of the white matter stained for NADPH-d, microtuble associated protein 2 or anterior cingulate gyrus and MD thalamic nuclei; 3) Collect, characterize and match additional brains from depressed patients and controls; 4) Following initial microarray analysis, conduct in situ hybridization studies to identify sites of expression of differentially altered mRNAs.

该中心项目的重点问题是，在抑郁症与对照组脑组织中，基因表达模式是否发生了差异性变化，以及这些信息是否可用于定义涉及背外侧前额叶皮层（DLPFC）、前扣带回和丘脑背内侧核（MD）的电路失调。要探讨的假设是，有一个中断的关联电路，涉及这些结构是神经发育为基础的，更敏感的表观遗传压力，记录到抑郁症的最初发作之前。一组新的数据表明，一个亚组的抑郁症患者有增加的心室大小，hypofrontality加上其他神经病理学发现类似于那些导致精神分裂症的神经发育假说。缺失是直接的神经病理学证据，例如在精神分裂症中发现的证据。我们报告说，三个神经元标记的胚胎皮质subplate量化尸检组织精神分裂症的大脑是异常分布相对于匹配的正常对照组，我们最近的数据牵连丘脑以及。皮质亚板，形成在第二个最直接的数据为精神分裂症的神经发育假说可以解释为缺陷的神经元迁移或程序性细胞死亡的亚板。一个积极的神经病理学发现可能代表一个重要的第一步，将支持抑郁症的神经发育假说，并将指出一个潜在的生产力集中在特定的大脑区域和分子进行研究与微阵列分析。一组独特的大脑从抑郁症和对照组已被收集，临床评估的历史，匹配的年龄，性别和自溶时间和最近开发的一种新方法的分析准备。具体的研究目标包括：1）定量和评估白色物质的间质神经元的形态，其被NADPH-d、微管相关蛋白2或前扣带回和MD丘脑核染色; 3）收集、表征和匹配来自抑郁症患者和对照的额外的大脑; 4）在初始微阵列分析之后，进行原位杂交研究以鉴定差异改变的mRNA的表达位点。