Dissecting sodium appetite circuits in the mammalian brain

剖析哺乳动物大脑中的钠食欲回路

• 批准号: 10458090
• 负责人: Yuki Oka
• 金额: $ 41.88万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458090
• 关键词: Action Potentials; Acute; Address; Aldosterone; Anatomy; Angiotensins; Animals; Appetite Regulation; Area; Behavior; Behavior Control; Biological Process; Blood; Brain; Cell Nucleus; Cells; Cognitive; Consumption; Desire for food; Dietary Sodium; Electrophysiology (science); Equilibrium; Feeding behaviors; Functional disorder; Genetic; Genetic Markers; Goals; Hemostatic function; Homeostasis; Hunger; Individual; Ingestion; Intake; Ions; Lamina Terminalis; Logic; Maps; Mediating; Modeling; Mole the mammal; Molecular; Molecular Genetics; Mus; Negative Valence; Neural Pathways; Neurons; Neurosciences; Nucleus solitarius; Osmoregulation; Pathway interactions; Physiological; Pilot Projects; Population; Population Control; Positive Valence; Process; Prosencephalon; Public Health; Publishing; Regulation; Research; Risk Factors; Role; Salts; Signal Transduction; Site; Sodium; Sodium Chloride; Synaptic Transmission; Techniques; Testing; Thirst; Vascular Cognitive Impairment; Viral; Virus; Water; Work; base; cardiovascular risk factor; cell type; craving; design; experimental study; gain of function; genetic information; hedonic; hindbrain; insight; locus ceruleus structure; loss of function; neural circuit; optogenetics; preference; relating to nervous system; tool; transcriptomics

Project Summary Internal sodium balance is critical for many physiological functions, including osmoregulation and action potentials. Deciphering the mechanisms that control sodium intake is essential for understanding the principles of appetite regulation and sodium homeostasis in the body. Our understanding of central sodium appetite regulation is still lacking compared to other appetite circuits such as thirst and hunger. I propose to study this fundamental brain circuit that controls our internal ion balance using transcriptomic and molecular genetic tools. Our preliminary and published results have identified specific neural populations in the mouse hindbrain and forebrain that acutely regulate sodium ingestion. However, it is currently unknown how these distinct neural nodes contribute to sodium appetite. Our central hypothesis is that distinct neural circuits regulate sodium appetite and tolerance. We will test this idea through three specific aims. In Aim 1, we will use gain- and loss-of-function manipulations to examine if individual neural populations control behavioral aversion and/or attraction toward sodium. This study is expected to identify the functional roles of each genetically defined neural population in sodium ingestion. In Aim 2, we propose to use genetics, virus tracing, and physiological recording to dissect the circuit organization underlying sodium ingestion. Once the anatomical map is identified, we will use projection specific neural perturbation to examine the function of the individual downstream regions. In Aim 3, we propose to identify cell types from downstream areas of sodium appetite neurons. We will achieve this by combining activity-dependent high-throughput single-cell transcriptomics and neural perturbation in the upstream population. This approach is expected to dissect specific cell types that receive sodium appetite signals from upstream neurons. We will then use genetic information of the identified downstream cell types to examine how signals from distinct nuclei interact to drive sodium appetite. Together, this proposal will provide critical insights into the brain-wide regulatory mechanisms underlying sodium ingestion.

项目概要 内部钠平衡对于许多生理功能至关重要，包括渗透压调节和作用 潜力。破译控制钠摄入量的机制对于理解钠摄入量至关重要 食欲调节和体内钠稳态的原理。我们对中枢的理解 与口渴和饥饿等其他食欲回路相比，钠的食欲调节仍然缺乏。我 提议利用转录组学来研究这种控制我们内部离子平衡的基本大脑回路 和分子遗传工具。我们的初步和发表的结果已经确定了特定的神经元 小鼠后脑和前脑中敏锐调节钠摄入的群体。然而，它是 目前尚不清楚这些不同的神经节点如何影响钠食欲。我们的中心假设 不同的神经回路调节钠的食欲和耐受性。我们将通过三个方面来测试这个想法 具体目标。在目标 1 中，我们将使用功能增益和功能丧失操作来检查个体神经元是否 人群控制对钠的行为厌恶和/或吸引力。这项研究预计将确定 每个基因定义的神经群在钠摄入中的功能作用。在目标 2 中，我们 提议利用遗传学、病毒追踪和生理记录来剖析电路组织 潜在的钠摄入。一旦确定了解剖图，我们将使用投影特定的神经网络 扰动来检查各个下游区域的功能。在目标 3 中，我们建议 识别钠食欲神经元下游区域的细胞类型。我们将通过结合来实现这一目标 上游活动依赖性高通量单细胞转录组学和神经扰动 人口。这种方法有望剖析接收钠食欲信号的特定细胞类型 来自上游神经元。然后，我们将使用已识别的下游细胞类型的遗传信息来 研究来自不同原子核的信号如何相互作用来驱动钠食欲。总之，该提案将 为钠摄入背后的全脑调节机制提供重要见解。