Neural circuits underlying thirst and satiety regulation

项目摘要 前脑结构终板(LT)在感觉体内水分平衡和 通过其下游神经回路调节口渴。最近的研究已经确定了基因定义的 控制饮酒开始的神经群组和回路组织。这些口渴的活动 在摄入水之前，随着水的消耗，神经元会迅速受到抑制。 这些结果表明，LT整合了动态平衡需求和实时饱腹感信号，以优化 喝酒。然而，人们对这种整合的功能意义和潜在的神经知之甚少。 电路。这些研究一直受到LT解剖结构的复杂性和缺乏遗传因素的阻碍 处理相关的神经回路。转录分析和神经学的最新技术进展 操作/映射工具为研究特定细胞类型的神经回路打开了一个令人兴奋的窗口 精确度。本研究结合了这些先进的方法来描绘细胞的组织 以及快速口渴的神经回路。这些研究建立在我们的结果基础上，即渴求神经元 在穹隆下器(SFO)，通过解剖学和时间上可分离的方式接收多个饱腹感信号 神经基质。在目标1中，我们将使用高通量单细胞rna-seq分析来阐明 大白鼠各核转录图谱。这项研究将提供一个框架，将个人 具有分子定义的细胞类型的LT的生理功能。根据我们的结果，我们将检查 口渴神经元是否包括LT中功能不同的多个亚群。在目标2中，我们将 描述由饮酒行为和渗透压引起的SFO中两个时间上不同的饱腹感信号 随水摄入量的变化。我们将确定携带个体口渴饱腹感信号的信号通路 采用灌胃输液和体内光学记录的方法，从清醒行为动物的SFO。在AIM 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神经回路 追踪和电生理工具。一旦我们确定了候选的大脑区域，我们将应用一种创新的 “单突触”scRNA-seq分析以确定富含在神经元中的特定基因 向SFO发送渗透压信号。该项目的成果将促进我们对神经基础的理解。 口渴和饱腹感的调节。

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.