NEUROPATHOLOGICAL & GENETIC ABNORMALITIES IN DEPRESSION

该中心提案的目的是将三个具有长期成功记录的高级研究人员组成的研究小组聚集在一起，专注于定义导致抑郁症中观察到的情感失调的细胞，生化和分子遗传病理学。每个小组都将利用创新技术。这将是一个巨大的、集中的努力，因为每个研究小组将使用来自同一组抑郁症患者和匹配对照的脑组织。人们普遍认为抑郁症与强烈的遗传成分、HPA轴的失调以及血清素代谢和生理的改变有关。此外，包括脑成像研究在内的大量新出现的数据表明，抑郁症患者的一个亚组有心室大小增加、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观察结果相似。需要探讨的具体假设是，在一个或多个反复涉及抑郁症的大脑结构（额叶皮质、前扣带回、中缝、蓝斑、下丘脑室旁核、海马体和中缝核）中存在遗传或表观遗传相关的神经发育异常。使用的方法包括免疫组织化学、原位杂交和微阵列DNA芯片技术。预计对LHPA应激轴、5HT系统和神经元迁移相关分子的研究将提示与微阵列芯片技术相关的特定大脑区域和基因的潜在生产重点。我们的理论是，从上述区域的多个位置评估数千个基因的水平和表达模式，将使我们能够确定抑郁症患者大脑中一致的失调模式。

The Purpose of this Center proposal is to bring to bring together three research groups of senior investigators with long, highly successful track records, to focus on defining the cellular, biochemical and molecular genetic pathology which contributes to the affective dysregulation observed at depressive illness. Innovative technology will be utilized by each group. This will represent a massive, concentrated effort in that each research team will use brain tissue from the same group of depressed patients and matched controls. There is broad consensus that depressive illness is associated with a strong genetic component, a dysregulation of the HPA axis and alterations in serotonin metabolism and physiology. In addition, a body of emerging data including that from brain imaging studies show that a subgroup of depressed patients have increased ventricular size, hypofrontality, plus other neuropathological findings similar to those observations that led to the neurodevelopmental hypothesis of schizophrenia. The specific hypothesis to be explored is that there is a genetic or epigenetic associated neurodevelopmental abnormality in one or more brain structures that have been repeatedly implicated in depressive illness [frontal cortex, anterior cingulate gyrus, raphe, locus coeruleus, paraventricular nucleus (PVN) of the hypothalamus, the hippocampus, and the raphe nuclei.] Methods to be utilized will include immunohistochemistry, in situ hybridization, and microarray DNA chip technologies. It is anticipated that the study of molecules associated with LHPA stress axis, the 5HT system and neuronal migration will suggest potentially productive foci on specific brain regions and genes to be investigated in association with the microarray chip technology. We theorize that assessing the levels and expression patterns of thousands of genes from a number of multiple sites in the regions listed above will allow us to identify a consistent pattern of dysregulation in the brains of depressed patients.