Neural circuits underlying thirst and satiety regulation

口渴和饱腹感调节的神经回路

• 批准号: 10240641
• 负责人: Yuki Oka
• 金额: $ 38.53万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240641
• 关键词: Anatomy; Animals; Appetite Regulation; Architecture; Area; Atlases; Automobile Driving; Behavior; Behavioral; Body Fluids; Body Water; Brain; Brain region; Cell Nucleus; Consummatory Behavior; Consumption; Data; Dehydration; Desire for food; Elderly; Electrophysiology (science); Environment; Equilibrium; Feedback; Feeding behaviors; Fiber; Fluid Balance; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Image; Individual; Infusion procedures; Ingestion; Knowledge; Label; Lamina Terminalis; Light; Link; Liquid substance; Logic; Mediating; Modeling; Molecular; Motivation; Mus; Neurons; Nutrient; Optics; Organ; Osmolalities; Outcome; Pathway interactions; Photometry; Physiological; Play; Polydipsia; Population; Process; Prosencephalon; Public Health; Recovery; Regulation; Research; Rewards; Role; Satiation; Sensory; Signal Pathway; Signal Transduction; Stimulus; Structure; Subfornical Organ; Symptoms; Testing; Thirst; Time; Viral; Water; Water consumption; absorption; alcohol use initiation; awake; base; cell type; drinking; drinking behavior; gastrointestinal; in vivo; innovation; insight; loss of function; neural circuit; relating to nervous system; single-cell RNA sequencing; thirst regulation; tool; transcriptomics

Project Summary A forebrain structure, lamina terminalis (LT), plays a key role in both sensing internal water balance and regulating thirst through its downstream neural circuits. Recent studies have identified genetically-defined neural populations and circuit organization that control the initiation of drinking. The activity of these thirst neurons are rapidly suppressed with the onset of water consumption prior to absorption of ingested water. These results suggest that the LT integrates the homeostatic need and real-time satiety signals to optimize drinking. However, little is known about the functional significance of such integration and the underlying neural circuits. These studies have been hindered by the anatomical complexity of the LT and the lack of genetic handle on related neural circuits. Recent technological advances in transcriptomic analysis and neural manipulation/mapping tools have opened up an exciting window to study neural circuit at cell-type-specific precision. The present study combines such advanced approaches to delineate the cellular organization of the LT and the neural circuitry underlying rapid thirst satiety. These studies build on our results that thirst neurons in the subfornical organ (SFO) receive multiple satiety signals through anatomically and temporally separable neural substrates. In Aim 1, we will employ high-throughput single-cell RNA-seq analysis to elucidate a transcriptomic atlas of individual nuclei of the LT. This study will provide a framework to link individual physiological functions of the LT with molecularly-defined cell types. Based on our results, we will examine whether thirst neurons comprise functionally distinct multiple subpopulations in the LT. In Aim 2, we will characterize two temporally distinct satiety signals in the SFO induced by drinking action and osmolality change by water intake. We will determine the signaling pathways that carry individual thirst satiety signals using intragustric fluid infusion and in vivo optical recording from the SFO in awake-behaving animals. In Aim 3, we will define the neural substrates and circuits that mediate osmolality-induced satiety by retrograde viral tracing and electrophysiological tools. Once we identify candidate brain areas, we will apply an innovative “monosynaptic” scRNA-seq analysis to identify specific genes enriched in the neurons that transmit the osmolality signal to the SFO. The outcome of this project will advance our understanding of neural basis of thirst and satiety regulation.

项目摘要 前脑结构（Lamina末端（LT））在感知内部水平衡和 通过其下游的神经回路调节第三。最近的研究已经确定了一般定义的 控制饮酒计划的神经种群和电路组织。这些第三的活动 在摄入水中，神经元因水的消耗而迅速抑制。 这些结果表明，LT整合了体内稳态需求和实时饱腹感，以优化 喝。但是，对于这种整合和基本中性的功能意义知之甚少 电路。这些研究受到LT的解剖复杂性的阻碍，缺乏遗传 处理相关的神经回路。转录组分析和神经元的最新技术进步 操纵/映射工具已经打开了一个令人兴奋的窗口，以研究细胞类型的神经回路 精确。本研究结合了描述细胞组织的高级方法 LT和基于快速的第三个饱腹感的神经元电路。这些研究以我们的结果为基础，即第三个神经元 在副骨器器官（SFO）中，通过解剖和临时分开接收多个饱腹感信号 神经底物。在AIM 1中，我们将采用高通量单细胞RNA-seq分析来阐明A LT单个核心的转录组图。这项研究将为链接个人提供一个框架 LT具有分子定义的细胞类型的生理功能。根据我们的结果，我们将检查 第三神经元是否在LT中完成功能上不同的多个亚群。在AIM 2中，我们将 饮酒动作和渗透压引起的SFO中的两个暂时不同的饱腹感信号表征 通过摄入量来改变。我们将确定带有单个第三个饱腹感信号的信号通路 使用内部液体输注和来自SFO的体内光学记录。目标 3，我们将定义通过逆行病毒介导渗透压诱导的饱腹感的神经底物和圆圈 跟踪和电生理工具。一旦我们确定了候选大脑区域，我们将应用创新 “单突触” SCRNA-seq分析，以鉴定富含神经元传播的特定基因 渗透压信号向SFO。该项目的结果将促进我们对神经基础的理解 第三和饱腹。