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仍然是精神病学研究中的一个相当大的挑战。调节失调的多巴胺能和应激通路似乎是重性抑郁症的促成因素;然而，很可能存在许多其他未识别的风险因素。在这里，我们建议调查抑郁症的分子病理学，使用微阵列实验，生物信息学分析和结果的解剖表征相结合的方法。我们的中心假设指出，抑郁症的生物易感性反映在一个持久的分子病理，是可检测的，在死后的人类大脑，并影响皮质边缘网络，其功能障碍可能会特别导致，或至少相关，抑郁症的情感成分。因此，基于显微解剖学和功能研究，我们将集中在这个情绪调节的皮层-边缘系统网络内的两个密集互连的大脑区域：i）杏仁核（AMY），作为对情绪的整合和表达至关重要的大脑区域，以及ii）前扣带皮层（ACC），因为抑郁相关的功能和形态变化一直在这个大脑区域被报道。由于显微解剖学研究表明，在这两个脑区的胶质细胞抑郁症相关的病理，我们将采用新的分析方法，分别评估与重度抑郁症相关的灰质内改变的胶质细胞或神经元功能的贡献。总之，这项研究提案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相关。所选基因的细胞核（AMY）和层状（ACC）变化模式的表征将提供解剖学信息，以生成基于网络的抑郁症分子病理学假说。公共卫生相关性：总体目标将是评估重性抑郁症病理生理学中生物学通路或细胞机制改变的因果关系，作为确定重性抑郁症新型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.