Neural circuits underlying thirst and satiety regulation

项目摘要 前脑结构，终板（LT），在感知内部水平衡和 通过下游的神经回路调节口渴。最近的研究发现， 控制饮酒开始的神经群和回路组织。这些干渴的活动 神经元在吸收摄入的水之前随着水消耗的开始而被迅速抑制。 这些结果表明，LT整合了稳态需求和实时饱腹感信号，以优化 喝酒然而，很少有人知道这种整合的功能意义和潜在的神经系统。 电路.这些研究受到LT解剖学复杂性和缺乏遗传学基础的阻碍。 处理相关的神经回路转录组学分析和神经系统疾病的最新技术进展 操纵/映射工具为研究细胞类型特异性的神经回路开辟了一个令人兴奋的窗口。 精度本研究结合了这些先进的方法来描绘细胞组织的 LT和快速口渴饱腹感的神经回路。这些研究建立在我们的结果之上， 在穹窿下器官（SFO）中，通过解剖学上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，我们将采用高通量单细胞RNA-seq分析来阐明 本研究将提供一个框架，以联系个人的LT核转录组图谱。 LT的生理功能与分子定义的细胞类型。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 描述了两个时间上不同的饱足信号在SFO诱导的饮用行动和渗透压 改变水的摄入。我们将确定携带个体口渴饱足信号的信号通路 在清醒的动物中使用胃内液体输注和来自SFO的体内光学记录。在aim中 3，我们将确定通过逆行病毒介导渗透压诱导的饱腹感的神经基质和回路， 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，以鉴定在传递突触的神经元中富集的特定基因。 向SFO发送渗透压摩尔浓度信号。该项目的成果将促进我们对神经基础的理解， 口渴和饱足调节。

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.