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

人类下丘脑的昼夜分子节律和双相情感障碍的参与

基本信息

批准号：
10491157
负责人：
Harry Pantazopoulos
金额：
$ 39.2万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491157
关键词：
Address Anxiety Area Autopsy Bipolar Disorder Brain Brain region Calcium Channel Cell Nucleus Cells Cessation of life Circadian Dysregulation Circadian Rhythms Clock protein Corticotropin-Releasing Hormone Data Development Diagnostic Disease Diurnal Rhythm Dopamine Foundations Functional disorder Gene Expression Genes Genetic Genetic Polymorphism Health Hour Human Hydrocortisone Hypothalamic structure Immunofluorescence Immunologic Impairment In Situ Hybridization Knowledge L-Type Calcium Channels Link Maps Measures Mental Depression Molecular Moods Neurons Neuropeptides Neurotransmitters Organism Output Pathology Patients Pattern Periodicity Phase Population Proxy Regulation Research Risk Rodent Role SSTR5 gene Sampling Severities Signal Transduction Signaling Molecule Somatostatin Stress Testing Therapeutic Time Treatment Efficacy Variant anxiety symptoms base biological adaptation to stress cell type circadian cohort depressive symptoms design disorder control emotion regulation genome wide association study human subject improved insight molecular clock mood regulation neural circuit neuropathology novel therapeutics paraventricular nucleus protein expression somatostatin receptor 5 suprachiasmatic nucleus time use virtual

项目摘要

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.

项目概要越来越多的证据支持昼夜节律功能障碍与双相情感障碍（BD）有关。那里目前迫切需要确定人类昼夜节律功能障碍的神经病理学相关性患有 BD 的受试者，并将这些与功能后果联系起来。我们专注于视交叉上核（SCN），哺乳动物生物的主时钟，其主要输出区域室旁核（PVN），一个与压力和焦虑调节密切相关的区域。我们的初步数据显示下降 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 中的节奏。此外，随着应激信号表达的增加，第 2 期的减少双相情感障碍患者早晨 PVN 中的促肾上腺皮质激素释放因子分子表明较弱的 SCN 节律影响下游应激信号，与已确定的增加一天中这个时候焦虑和抑郁的严重程度以及皮质醇的增加。对夜间活动的啮齿动物的研究深入了解 SCN 和 PVN 如何参与调节压力和情绪，表明受到干扰的 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律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 BD 受试者的 SCN 支持这一假设。目前缺乏相关信息神经肽和时钟分子的细胞特异性表达节律及其与压力的关联人类这些区域的反应分子。拟议的研究将奠定必要的基础检验我们的总体假设，即 BD 中 SCN 分子钟节律的改变与生物钟节律改变，下游区域应激反应分子表达增加压力反应和情绪调节。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类 SCN 中的表达昼夜节律， PVN ii) BD 患者的 SCN 和 PVN 分子节律被破坏，与表达改变相关涉及全基因组关联研究的分子。