Diurnal Molecular Rhythms of the Human Hypothalamus and Involvement in Bipolar Disorder

项目摘要 越来越多的证据支持昼夜节律功能障碍参与双相情感障碍（BD）。那里 目前迫切需要鉴定人类昼夜节律功能障碍的神经病理学相关性 与BD的主题，并将这些相关的功能后果。我们专注于视交叉上 核（SCN），哺乳动物生物体的主时钟，其主要输出区域为室旁核 (PVN)这一区域与压力和焦虑的调节密切相关。初步数据显示 SCN中生长抑素和时钟蛋白周期2的表达表明SCN分子时钟受损 BD的节奏。此外，周期2沿着减少，应激信号的表达增加， 双相情感障碍受试者早晨室旁核中促肾上腺皮质激素释放因子分子的表达表明 较弱的SCN节律会影响下游的应激信号，这与已建立的 焦虑和抑郁的严重程度以及每天这个时候皮质醇的增加。对夜行啮齿动物的研究表明， 提供了关于SCN和PVN如何参与调节压力和情绪的见解，这表明， SCN分子钟节律可以改变生物钟分子和应激反应分子的表达节律 参与情绪调节的区域。我们的初步证据表明， BD受试者SCN的变化支持这一假设。目前缺乏关于 神经肽和时钟分子的细胞特异性表达节律及其与应激的关系 这些区域的反应分子。拟议的研究将建立必要的基础， 为了验证我们的总体假设，即BD中SCN中分子钟节律的改变与以下因素有关： 生物钟节律改变，下游相关区域应激反应分子表达增加 在压力反应和情绪调节方面。我们将测试以下假设：i）时钟分子的表达， 神经肽和促肾上腺皮质激素释放因子遵循人SCN中表达的昼夜节律， ii）在患有BD的受试者中SCN和PVN分子节律被破坏，与改变的表达相关 与全基因组关联研究有关的分子。

Project Summary Accumulating evidence supports the involvement of circadian rhythm dysfunction in bipolar disorder (BD). There is currently a critical need for identifying the neuropathological correlates of circadian dysfunction in human subjects with BD, and linking these correlates to functional consequences. We focus on the suprachiasmatic nucleus (SCN), the master clock of mammalian organisms, and its major output area the paraventricular nucleus (PVN), a region critically involved in the regulation of stress and anxiety. Our preliminary data showing decreased expression of somatostatin and the clock protein period 2 in the SCN indicate impaired SCN molecular clock rhythms in BD. Furthermore, decreased period 2 along with increased expression of the stress signaling molecule corticotropin releasing factor in the PVN during the morning in subjects with bipolar disorder suggests that weaker SCN rhythms impact downstream stress signaling, coinciding with the established increase in severity of anxiety and depression and increased cortisol at this time of day. Studies in nocturnal rodents have provided insight into how the SCN and PVN are involved in regulating stress and mood, suggesting that disrupted SCN molecular clock rhythms can alter expression rhythms of clock molecules and stress response molecules in regions involved in mood regulation. Our preliminary evidence suggesting weakened molecular clock rhythms in the SCN of subjects with BD supports this hypothesis. There is currently a lack of information regarding the cell specific expression rhythms of neuropeptides and clock molecules, and their association with stress response molecules in these regions in humans. The proposed studies will establish the foundation necessary to test our overarching hypothesis that altered molecular clock rhythms in the SCN in BD are associated with altered clock rhythms and increased expression of stress response molecules in downstream regions involved in stress response and mood regulation. We will test the hypotheses that i) expression of clock molecules, neuropeptides, and corticotropin releasing factor follow diurnal rhythms of expression in the human SCN and PVN ii) SCN and PVN molecular rhythms are disrupted in subjects with BD, associated with altered expression of molecules implicated in genome wide association studies.