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

• 批准号: 10685498
• 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
• 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/10685498
• 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; Somatostatin Receptor; Stress; Testing; Therapeutic; Time; Treatment Efficacy; Variant; anxiety symptoms; biological adaptation to stress; cell type; circadian; cohort; depressive symptoms; design; 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

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.

项目摘要 积累的证据支持昼夜节律功能障碍在躁郁症（BD）中的参与。那里 目前是确定人类昼夜节律功能障碍的神经病理学相关性的关键需求 具有BD的受试者，并将这些相关性与功能后果联系起来。我们专注于肩部 核（SCN），哺乳动物生物的主时钟及其主要输出区域 （PVN），一个严重涉及压力和焦虑的地区。我们的初步数据显示减少 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，周期2的减少以及应力信号的表达增加 躁郁症受试者的早晨，PVN中的分子皮质激素释放因子表明 较弱 焦虑和抑郁的严重程度以及每天的这个时候皮质醇增加。夜间啮齿动物的研究 提供了有关SCN和PVN如何参与调节压力和情绪的洞察力，这表明这被破坏了 SCN分子时钟节奏可以改变时钟分子的表达节奏和应力响应分子 在涉及情绪调节的地区。我们的初步证据表明分子时钟节奏减弱 在具有BD的受试者的SCN中，支持了这一假设。目前缺乏有关 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联 这些区域中人类的反应分子。拟议的研究将确定必要的基础 为了测试我们的总体假设，即BD中SCN中的分子时钟节奏改变与 时钟节奏的改变和下游区域中应力反应分子的表达增加 在压力反应和情绪调节中。我们将测试i）时钟分子的表达的假设， 神经肽和皮质激素释放因子遵循人类SCN的表达昼夜节奏 PVN II）SCN和PVN分子节律在患有BD的受试者中被破坏，与表达改变有关 与基因组广泛关联研究有关的分子。

项目成果

Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder.

• DOI: 10.3389/fnins.2022.903941
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Valeri, Jake;O'Donovan, Sinead M.;Wang, Wei;Sinclair, David;Bollavarapu, Ratna;Gisabella, Barbara;Platt, Donna;Stockmeier, Craig;Pantazopoulos, Harry
• 通讯作者: Pantazopoulos, Harry