NEUROPATHOLOGICAL & GENETIC ABNORMALITIES IN DEPRESSION

该中心提案的目的是将具有长期、高度成功的记录的三个高级研究人员研究小组聚集在一起，专注于定义导致抑郁症所观察到的情感失调的细胞、生化和分子遗传病理。每个小组都将利用创新技术。这将代表着一项大规模的、集中的努力，因为每个研究团队都将使用同一组抑郁症患者和匹配的对照组的脑组织。人们普遍认为，抑郁症与强大的遗传成分、HPA轴的失调以及5-羟色胺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兴数据显示，一组抑郁症患者的脑室大小、额叶下移，以及其他类似于导致精神分裂症神经发育假说的观察结果的神经病理结果。有待探索的具体假设是，在反复涉及抑郁症的一个或多个脑结构[额叶皮质、前扣带回、中缝、蓝斑、下丘脑室旁核(PVN)、海马体和中缝核团]中存在遗传或表观遗传学相关的神经发育异常。将利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。预计对与LHPA应激轴、5-羟色胺系统和神经元迁移相关的分子的研究将建议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性焦点。我们的理论是，评估来自上述区域多个位置的数千个基因的水平和表达模式，将使我们能够识别抑郁症患者大脑中一致的调节失调模式。

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.