Project 1: Distinct Neural Phenotypes in Bipolar & Major Depression

该中心申请提出了两个相关的中心假设。最主要的假设是，两种最严重的精神疾病，双相情感障碍(BPD)和严重抑郁障碍(MDD)在大脑中具有不同的神经表型或生物学特征，这是通过一组不重叠的单个基因或功能相关基因集合表达变化的模式来识别的。第二种假设是，一组较小的基因将在这两种疾病中显示出共同的表达变化，并可能代表与共同的脆弱性或大脑对这些疾病的共同反应有关的机制。这项拨款提案将确认、表征和研究与BPD和MDD密切相关的选定基因和途径，并与对照组和包括成纤维细胞在内的精神分裂症(SZ)进行对比 生长因子系统相关基因和线粒体功能相关基因。我们将通过检查涉及丘脑-皮质配对结构的关键回路中基因的协调表达和调控来扩展我们对已识别基因的研究，测试它们在大鼠和小鼠情绪性模型中的功能相关性，通过检测启动子变体来研究表达改变的可能机制，并研究两个强烈相关的系统，成纤维细胞生长因子和线粒体。此外，为了更全面地确定与这两种疾病相关的不同神经表型，人类尸检 研究将扩展到更多的边缘结构，目前队列中的预测将在一组新的BPD和MDD队列中进行测试，并与对照组进行对比。确认一组可预测MDD不同于BPD的有效和复制的基因和途径将对研究和确定这些疾病的病因和确定其治疗或预防的新靶点做出重大贡献。

This Center application proposes two related central hypotheses. The pdmary hypothesis is that two of the most serious mental illnesses, bipolar disorder (BPD) and major depressive disorder (MDD) have distinct neurophenotypes or biological signatures in the brain as identified by a set of non-overlapping patterns of altered expression of individual genes or functionally-related ensembles of genes. The secondary hypothesis is that a smaller set of genes will show common alterations in expression in the two diseases and may represent mechanisms relating to common vulnerability or a common response in the brain to these disorders. This grant proposal will confirm, characterize and study selected genes and pathways which are strongly implicated in BPD and MDD contrasted with controls and schizophrenics (SZ) including fibroblast growth factor (FGF) system-related genes and genes involved in mitochondrial function. We will extend our studies of the identified genes by examining the coordinated expression and regulation of the genes in the context of a critical circuit involving thalamo-cortical paired structures, test their functional relevance in rat and in mouse models of emotionality, investigate possible mechanisms of altered expression by examining promoter variants and study two strongly implicated systems, FGF and mitochondria. In addition, in order to more fully define the distinct neurophenotypes associated with these two disorders, the human postmortem studies will be expanded to additional limbic structures and the predictions adsing in the current cohorts will be tested in a new set of BPD and MDD cohorts contrasted with controls. The identification of a validated and replicated set of genes and pathways that could predict MDD as distinct from BPD would constitute a ;major contribution for investigating and for identifying the etiology of these disorders and identify novel targets for their treatment or prevention.