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双相情感障碍与昼夜节律紊乱的关系。那里 目前迫切需要确定人类昼夜节律紊乱的神经病理相关性。 受试者患有BD，并将这些与功能后果联系起来。我们把重点放在视交叉上 哺乳动物的主钟--核团(SCN)及其主要输出区--室旁核 室旁核(PVN)，一个与压力和焦虑的调节密切相关的区域。我们的初步数据显示 生长抑素和时钟蛋白周期2在SCN中的表达提示SCN分子时钟受损 BD的节律。此外，随着胁迫信号表达的增加，周期2缩短 双相情感障碍受试者早上室旁核促肾上腺皮质激素释放因子分子提示 较弱的SCN节律影响下游应激信号，与已建立的 在一天中的这个时候，焦虑和抑郁的严重性以及皮质醇的增加。对夜间活动的啮齿动物的研究 提供了关于SCN和PVN如何参与调节压力和情绪的洞察，表明这种干扰 SCN分子时钟节律可以改变时钟分子和应激反应分子的表达节奏 在涉及情绪调节的区域。我们的初步证据表明分子时钟节律减弱 在BD受试者的SCN中支持这一假设。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 人类这些区域的反应分子。拟议的研究将奠定必要的基础 为了测试我们的主要假设，即BD患者SCN中分子时钟节律的改变与 相关下游区域时钟节律改变和应激反应分子表达增加 在压力反应和情绪调节方面。我们将测试这样的假设：i)时钟分子的表达， 神经肽和促肾上腺皮质激素释放因子在人SCN和 BD患者PVN II)SCN和PVN分子节律紊乱，与表达改变相关 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.