NEUROBIOLOGICAL BRAIN ABNORMALITIES IN DEPRESSIVE ILLNESS

该中心项目关注的问题是，在抑郁和正常的脑组织中，基因表达模式是否发生了不同的变化，以及这些信息是否可以用来定义涉及背外侧前额叶皮层（DLPFC）、前扣带回和丘脑中腰核（MD）的回路失调。要探索的假设是，在涉及这些结构的联想回路中存在破坏，这些结构是基于神经发育的，对表观遗传压力更敏感，这是在抑郁症最初发作之前记录的。大量新出现的数据表明，抑郁症患者的一个亚组有心室增大、前额叶下位以及其他神经病理发现，这些发现与导致精神分裂症神经发育假说的那些相似。缺少的是直接的神经病理学证据，比如在精神分裂症中发现的证据。我们报道了在精神分裂症大脑死后组织中量化的胚胎皮层亚板的三个神经元标记物相对于匹配的正常对照分布异常，我们最近的数据也涉及丘脑。在精神分裂症神经发育假说的第二个最直接数据期间形成的皮质亚板可以解释为神经元迁移缺陷或亚板中的程序性细胞死亡。一个积极的神经病理学发现可能代表着重要的第一步，将支持抑郁症的神经发育假说，并将指向一个潜在的富有成效的重点，即与微阵列分析相关的特定大脑区域和分子的研究。从抑郁症患者和对照组中收集了一组独特的大脑，通过历史进行临床评估，匹配年龄，性别和自溶时间，并准备用最近开发的新方法进行分析。具体的研究目的包括：1)定量和评估NADPH-d、微管相关蛋白2染色的白质间质神经元或前扣带回和MD丘脑核的形态；3)从抑郁症患者和对照组中收集、表征和匹配额外的大脑；4)在初始微阵列分析之后，进行原位杂交研究，以确定差异改变mrna的表达位点。

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.