The Effect of mWAKE in the Subfornical Organ on the Circadian Regulation of Water Consumption

穹窿下器官 mWAKE 对耗水量昼夜节律调节的影响

基本信息

批准号：
10464743
负责人：
Elijah Blank
金额：
$ 4.68万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-23 至 2025-05-22
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464743
关键词：
Address Animals Area Arousal Behavior Biological Clocks Biological Rhythm Biomedical Research Brain Brain region Cells Circadian Dysregulation Circadian Rhythms Darkness Data Dependovirus Development Drosophila genus Exhibits Feedback Fluid Balance Future Gene Expression Genes Genetic Screening Genetic Transcription Glutamates Health Human Impairment Invertebrates Kidney Knock-out Label Lead Light Liver Luciferases Mammals Mediating Mentors Molecular Mus Nature Neurons Organ Organism Orthologous Gene Outcome Study Output Pathway interactions Pattern Periodicity Physiological Processes Physiology Positioning Attribute Process Research Personnel Sleep Slice Solid Students Subfornical Organ System Technical Expertise Thirst Time Tissues Training Transgenic Mice Virus Visceral Water Water consumption Western Blotting Work awake career cell type circadian circadian pacemaker circadian regulation designer receptors exclusively activated by designer drugs drinking drinking behavior experimental study fly gamma-Aminobutyric Acid insight molecular clock motivated behavior mutant patch clamp receptor shift work single cell sequencing success suprachiasmatic nucleus

项目摘要

Project Summary/Abstract Circadian rhythms are important for human health. At a molecular level, they are controlled by a cell-autonomous molecular clock which is generally synchronized across different tissues. In mammals, these local clocks are coordinated by the suprachiasmatic nucleus (SCN), the circadian pacemaker. Most previous work in this field has focused on how the SCN regulates neuronal physiology and behavior, and the function of local clocks in these processes is relatively understudied. In particular, the functions of extra-SCN oscillators in the brain are poorly understood. Our lab previously identified a molecule Wide Awake (WAKE) in Drosophila, which acts downstream of the clock to reduce arousal at night by inhibiting neuronal activity in a cell-autonomous manner. WAKE is conserved from flies to mammals, including mice and humans. In mice, our lab has recently found that WAKE in mice is enriched in the subfornical organ (SFO). This brain region is known to regulate behaviors controlling fluid balance and water consumption. Moreover, the SFO has been shown to exhibit robust cycling of local clock oscillators, and furthermore water consumption is under circadian control. My preliminary data suggest that loss of mWAKE results in an increase in drinking, specifically during the night. Taken together, these findings lead me to hypothesize that mWAKE normally inhibits thirst-promoting SFO neurons at night. Because SCN-specific mechanisms have also been shown to regulate circadian aspects of drinking, this system may allow for characterization of the interplay between local and central clock mechanisms in regulating a motivated behavior. In Aim 1, I propose to examine whether mWAKE expression in the SFO is rhythmic and under clock control and to characterize the nature of mWAKE+ cells in the SFO. In Aim 2, I will investigate the effects of mWAKE on SFO neuronal activity and the function of mWAKE and mWAKE+ cells in regulating rhythmic water consumption. These studies should provide new insights into how local clocks help tune neuronal activity to modulate rhythmic behaviors. Because desynchrony between local body clocks and the SCN can be produced by common activities such as shift work and is likely associated with poor health outcomes, these studies may one day inform future therapies related to dysregulation of circadian clocks. Finally, the proposed experiments will provide a solid platform for me to strengthen my technical skills and conceptual background and, combined with my proposed training in career and professional development, will position me for future success as an independent investigator and a mentor for diverse students in biomedical research.

项目概要/摘要昼夜节律对人类健康很重要。在分子水平上，它们由细胞自主控制分子钟通常在不同组织之间同步。在哺乳动物中，这些本地时钟是由视交叉上核（SCN）（昼夜节律起搏器）协调。该领域之前的大部分工作重点关注 SCN 如何调节神经元生理和行为，以及局部时钟的功能这些过程的研究相对较少。特别是，大脑中额外 SCN 振荡器的功能是不太了解。我们的实验室之前在果蝇中发现了一种分子“完全清醒”（WAKE），其作用是生物钟的下游，通过以细胞自主的方式抑制神经元活动来减少夜间的觉醒。 WAKE 从果蝇到哺乳动物（包括小鼠和人类）都是保守的。我们的实验室最近在小鼠身上发现小鼠的 WAKE 在穹窿下器官 (SFO) 中丰富。众所周知，这个大脑区域可以调节行为控制液体平衡和水消耗。此外，SFO 已被证明表现出强劲的循环本地时钟振荡器，此外，水的消耗受到昼夜节律的控制。我的初步数据表明 mWAKE 的丧失会导致饮酒量增加，特别是在夜间。综合起来，这些发现使我推测 mWAKE 通常会在夜间抑制促进口渴的 SFO 神经元。由于 SCN 特异性机制也已被证明可以调节饮酒的昼夜节律，因此该系统可以允许描述本地时钟机制和中央时钟机制之间的相互作用的特征动机行为。在目标 1 中，我建议检查 SFO 中的 mWAKE 表达是否有节奏且在时钟控制下并表征 SFO 中 mWAKE+ 单元的性质。在目标 2 中，我将调查 mWAKE对SFO神经元活动的影响以及mWAKE和mWAKE+细胞的调节功能有节奏的用水。这些研究应该为本地时钟如何帮助调节神经元提供新的见解调节节律行为的活动。因为局部生物钟和 SCN 之间的不同步可以由轮班工作等常见活动产生，并且可能与不良健康结果相关，这些有一天，研究可能会为未来与生物钟失调相关的治疗提供信息。最后，提出的实验将为我提供一个坚实的平台，以加强我的技术技能和概念背景并且，结合我提议的职业和专业发展培训，将为我的未来做好准备作为一名独立研究者和生物医学研究领域不同学生的导师，取得了成功。