A pathway linking gut osmolarity to thirst

项目总结/摘要 液体摄入量被精确调节以满足生理需求。这对于维持体液平衡至关重要 最终是为了生存，尽管对潜在的机制仍然知之甚少。关键是，身体 需要能够感知摄入液体的渗透压，因为不同的渗透压可能具有相反的 对生理需求和行为反应的影响。最近的研究表明， 胃肠道是实时检测液体渗透压并将其与中枢口渴进行通信的场所 神经回路，但这种感觉背后的具体机制是完全未知的。 该建议的目的是确定检测渗透压的关键细胞类型和传入神经通路， 并将此信息传递给大脑以控制口渴。这里提出的假设是， 分两步首先，肠道中专门的化学感受细胞，称为肠内分泌细胞， 肠腔的渗透压。然后这些细胞通过激活邻近的迷走神经感觉神经与大脑交流 神经元目的1将确定肠内分泌细胞在口渴和口渴感中的作用，而目的2将确定肠内分泌细胞在口渴和口渴感中的作用。 专注于迷走神经这些实验将使用遗传和病毒介导的工具来完成， 并首次在清醒的行为小鼠中操纵特定的肠内分泌和迷走神经细胞类型。的 将测量操纵这些细胞类型对液体摄入的影响，以及相应的口渴活动。 在穹窿下器官中追踪肠渗透压的神经元将在体内使用钙成像来监测。 这些数据将揭示基本的机制，使身体适当地回应摄入 物质和维持流体稳态。最终，这些实验将促进我们对 肠道中的基本生理过程以及身体如何处理液体和盐;这些过程的失调 这些过程会导致高血压和胃肠道疾病等疾病。

PROJECT SUMMARY/ABSTRACT Fluid intake is precisely regulated to match physiological need. This is imperative to maintain fluid homeostasis and ultimately for survival, although the underlying mechanisms remain poorly understood. Critically, the body needs to be able to sense the osmolarity of ingested fluids, as different osmolarities can have opposing impacts on physiological need and behavioral responses. It has been recently demonstrated that the gastrointestinal tract is the locale that detects and communicates fluid osmolarity in real-time to central thirst circuits, but the specific mechanisms underlying this osmosensation are completely unknown. The aim of this proposal is to identify the key cell types and afferent neural pathways that detect osmolarity in the gut and relay this information to the brain to control thirst. The hypothesis proposed here is that this happens in two steps. First, specialized chemosensory cells in the gut, called enteroendocrine cells, detect the osmolarity of the gut lumen. These cells then communicate with the brain by activating adjacent vagal sensory neurons. Aim 1 will determine the role of enteroendocrine cells in thirst and osmosensation, whereas Aim 2 will focus on the vagus nerve. These experiments will be done using genetic and virally mediated tools to target and manipulate, for the first time, specific enteroendocrine and vagal cell types in awake, behaving mice. The effect manipulating these cell types has on fluid intake will be measured, and the corresponding activity of thirst neurons in the subfornical organ that track gut osmolarity will be monitored using calcium imaging in vivo. These data will reveal fundamental mechanisms that allow the body to appropriately respond to ingested substances and maintain fluid homeostasis. Ultimately, these experiments will advance our understanding of basic physiologic processes in the gut and how fluid and salt are handled by the body; dysregulation of these processes contributes to conditions like hypertension and gastrointestinal disorders.