Transcriptome analysis in major depression

描述（由申请人提供）：尽管情绪障碍带来了巨大的个人和经济负担，但了解这些疾病的病理和分子特征仍然是精神病学研究中的一个相当大的挑战。失调的血清素能和应激途径似乎是导致重度抑郁症（MOD）的因素；然而，可能存在许多其他未确定的风险因素。在这里，我们建议采用微阵列实验、生物信息学分析和结果解剖表征相结合的方法来研究MOD的分子病理学。我们的中心假设认为，MOD的生物易感性反映在死后人类大脑中可检测到的持续分子病理中，并影响皮质边缘网络，其功能障碍可能特别导致MOD的情感成分，或至少与之相关。因此，基于微观解剖和功能研究，我们将集中研究MOD皮质边缘网络中两个紧密相连的大脑区域：1)杏仁核（amy扁桃体），作为一个对情绪整合和表达至关重要的大脑区域；2)前扣带皮层（ACC），因为mdd相关的功能和形态学变化一直在该大脑区域被报道。重要的是，在AMY中没有基因表达谱研究的报道，因此在AMY和ACC之间没有MOD潜在分子相关的比较分析，特别是在神经精神疾病的背景下。由于显微解剖研究表明这两个脑区存在与MDD相关的神经胶质病理，我们将应用新的分析方法分别评估灰质中与MDD相关的神经胶质或神经元功能改变的贡献。本研究计划的结果可能揭示所有MDD受试者中常见的一般途径和/或可能因性别和MDD家族史而不同的特定途径，这两个因素与不同的MMD表型特征相关。结果还将确定几种疾病因素对MDD转录组相关的潜在贡献，包括自杀死亡、共病酒精依赖或抗抑郁治疗。选定基因的核（AMY）模式和层状（ACC）变化的特征将提供解剖学信息，以产生基于网络的MDD分子病理学假设。

DESCRIPTION (provided by applicant): Despite the substantial personal and economic burden of mood disorders, understanding the pathological and molecular features of these disorders remains a considerable challenge in psychiatric research. Dysregulated serotonergic and stress pathways appear to be contributing factors in major depressive disorder (MOD); however, it is likely that numerous other unidentified risk factors exist. Here we propose to investigate the molecular pathology of MOD, using a combined approach of microarray experiments, bioinformatic analysis and anatomical characterization of results. Our central hypothesis states that the biological liability to MOD is reflected in a persistent molecular pathology that is detectable in the postmortem human brain and that affects a cortico-limbic network, whose dysfunction might specifically cause, or at least correlate with, the affective component of MOD. Hence, based on microanatomical and functional studies, we will concentrate on two densely interconnected brain areas within this cortical-limbic network of MOD: i) the amygdala (AMY), as a brain region that is crucial to the integration and expression of emotions, and ii) the anterior cingulate cortex (ACC), as MDD-related functional and morphological changes have been consistently reported in this brain area. Importantly, no gene expression profiling studies have been reported in the AMY, and by extension no comparative analysis of potential molecular correlates of MOD have been reported between the AMY and ACC, especially in the context of neuropsychiatric disorders. As microanatomical studies suggest a glial MDD-related pathology in these two brain areas, we will apply novel analytical approaches to separately assess the contribution of altered glial or neuronal functions within the gray matter in correlation with MDD. Results from this research proposal could reveal either a general pathway that is common among all MDD subjects and/or specific pathways that may differ as a function of sex and family history of MDD, two factors that are associated with different phenotypic features of MMD. Results will also determine the potential contribution of several disease factors to the transcriptome correlates of MDD, including death by suicide, co-morbid alcohol dependence or antidepressant treatment. The characterization of patterns of nuclei (AMY) and laminar (ACC) changes for selected genes will provide anatomical information to generate network-based hypotheses on the molecular pathology of MDD.