Project 1: Distinct Neural Phenotypes in Bipolar & Major Depression

本中心的申请提出了两个相关的中心假设。pdmary假说认为，两种最严重的精神疾病，双相情感障碍（BPD）和重度抑郁症（MDD）在大脑中具有不同的神经表型或生物学特征，可以通过个体基因或功能相关的基因集合的改变表达的一组非重叠模式来识别。第二种假设是，在这两种疾病中，一组较小的基因会显示出共同的表达改变，可能代表了与大脑对这些疾病的共同脆弱性或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（与对照组和精神分裂症（包括成纤维细胞）相比）密切相关的选定基因和途径

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.