Molecular characterization of a corticolimbic network in 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的因素；然而，可能存在许多其他未确定的风险因素。在此，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重度抑郁症的分子病理学。我们的中心假设认为，对重度抑郁症的生物学倾向反映在一种持续的分子病理中，这种病理在死后的人类大脑中可以检测到，并影响皮质边缘网络，其功能障碍可能特别导致抑郁症的情感成分，或者至少与之相关。因此，基于微观解剖和功能研究，我们将集中研究情绪调节皮层边缘网络中两个紧密相连的大脑区域：1)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；2)前扣带皮层（ACC），因为抑郁症相关的功能和形态学变化一直在该大脑区域被报道。由于显微解剖研究表明这两个脑区存在与神经胶质抑郁相关的病理，我们将应用新的分析方法分别评估灰质内神经胶质或神经元功能改变与重度抑郁症的关系。总之，这项研究计划的结果可以揭示所有抑郁症受试者中常见的一般途径和/或可能因性别和重度抑郁症家族史的功能而不同的特定途径，这两个因素与抑郁症的不同表型特征相关。选定基因的核（AMY）和层状（ACC）变化模式的表征将提供解剖学信息，以产生基于网络的抑郁症分子病理学假设。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，作为确定重度抑郁症新治疗干预的潜在线索的重要步骤。

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.