NEUROBIOLOGICAL BRAIN ABNORMALITIES IN DEPRESSIVE ILLNESS

该中心的研究重点是抑郁和对照脑组织的基因表达模式是否发生了差异变化，以及这一信息是否可以用来定义涉及前额叶背外侧皮质(DLPFC)、前扣带回和丘脑内侧核(MD)的回路失调。有待探索的假设是，涉及这些结构的联合回路存在中断，这些结构是基于神经发育的，对表观遗传压力更敏感，这些压力被记录为在抑郁症最初发作之前。大量新出现的数据显示，一组抑郁症患者的脑室大小、额叶下移以及其他神经病理结果与导致精神分裂症神经发育假说的结果相似。缺失是直接的神经病理证据，例如在精神分裂症中发现的证据。我们报道了精神分裂症患者死后脑组织中胚胎皮质亚板的三个神经元标记物相对于匹配的正常对照是异常分布的，我们最近的数据也涉及丘脑。在精神分裂症的神经发育假说的第二直接数据期间形成的皮质亚板可以被解释为亚板中神经元迁移或程序性细胞死亡的缺陷。阳性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，并将指向与微阵列分析相关联的特定大脑区域和分子的潜在生产性重点。从抑郁症和对照组受试者中收集了一组独特的大脑，通过临床历史进行评估，在年龄、性别和自溶时间上匹配，并准备用最近开发的一种新方法进行分析。具体的研究目标包括1)定量和评估NADPH-d、微管相关蛋白2或前扣带回和MD丘脑核团染色的白质间质神经元的形态；3)收集、鉴定和匹配抑郁症患者和对照组的额外大脑；4)在进行初步的微阵列分析之后，进行原位杂交研究以确定差异改变的mRNAs的表达部位。

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.