Molecular characterization of a corticolimbic network in depression

描述(由申请人提供)：尽管情绪障碍给个人和经济带来了巨大的负担，但理解这些障碍的病理和分子特征在精神病学研究中仍然是一个相当大的挑战。调节失调的5-羟色胺能和应激途径似乎是导致严重抑郁症的因素；然而，很可能存在许多其他未确定的危险因素。在这里，我们建议使用基因芯片实验、生物信息学分析和结果的解剖学特征相结合的方法来研究重度抑郁症的分子病理学。我们的中心假设是，抑郁症的生物易感性反映在一种持久的分子病理中，这种病理可以在死后的人类大脑中检测到，并影响皮质-边缘网络，其功能障碍可能特定地导致或至少与抑郁症的情感成分相关。因此，在显微解剖学和功能研究的基础上，我们将集中在情绪调节的皮质-边缘网络中两个紧密相连的大脑区域：i)杏仁核(AMY)，作为一个对情绪整合和表达至关重要的大脑区域；以及ii)前扣带皮质(ACC)，因为与抑郁相关的功能和形态变化在该大脑区域一直被报道。由于显微解剖学研究表明这两个脑区与胶质抑制相关的病理，我们将应用新的分析方法来分别评估灰质内胶质或神经元功能改变与重度抑郁的相关性。总而言之，这项研究建议的结果可能揭示出在所有抑郁症受试者中普遍存在的一般途径和/或可能因性别和重度抑郁症家族史而不同的特定途径，这两个因素与抑郁症的不同表型特征有关。所选基因的核(AMY)和板层(ACC)变化模式的特征将为产生基于网络的抑郁症分子病理假说提供解剖学信息。公共卫生相关性：总体目标将是评估重度抑郁症病理生理学中改变的生物途径或细胞机制的因果关系，作为确定重型抑郁症新的治疗干预措施的潜在线索的关键步骤。

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 depression; however, it is likely that numerous other unidentified risk factors exist. Here we propose to investigate the molecular pathology of major depression, using a combined approach of microarray experiments, bioinformatic analysis and anatomical characterization of results. Our central hypothesis states that the biological liability to major depression 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 depression. Hence, based on microanatomical and functional studies, we will concentrate on two densely interconnected brain areas within this cortical- limbic network of mood regulation: 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 depression-related functional and morphological changes have been consistently reported in this brain area. As microanatomical studies suggest a glial depression-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 major depression. Together, results from this research proposal could reveal either a general pathway that is common among all depressed subjects and/or specific pathways that may differ as a function of sex and family history of major depression, two factors that are associated with different phenotypic features of depression. 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 depression. PUBLIC HEALTH RELEVANCE: The overall goal will be to assess causality of altered biological pathways or cellular mechanisms in the pathophysiology of major depression, as an essential step in identifying potential leads for novel therapeutic intervention in major depression.