A pathway linking gut osmolarity to thirst

项目摘要/摘要 液体摄入量经过精确调节，以满足生理需要。这对于维持液体动态平衡是必不可少的。 最终是为了生存，尽管潜在的机制仍然鲜为人知。关键的是，身体 需要能够感觉到摄入的液体的渗透压，因为不同的渗透压可以有相反的 对生理需求和行为反应的影响。最近已经证明， 胃肠道是实时检测液体渗透压并将其传递给中枢口渴的场所 电路，但这种渗透感觉背后的具体机制完全未知。 这一建议的目的是确定检测脑内渗透压的关键细胞类型和传入神经通路。 并将这些信息传递给大脑，以控制口渴。这里提出的假设是，这是 发生在两个步骤中。首先，肠道中特殊的化学感觉细胞，称为肠内分泌细胞，检测 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与大脑进行交流 神经元。目标1将确定肠内分泌细胞在口渴和渗透感觉中的作用，而目标2将确定 重点放在迷走神经上。这些实验将使用基因和病毒介导的工具来靶向 并首次在清醒、行为正常的小鼠中操纵特定的肠道内分泌和迷走神经细胞类型。这个 操纵这些细胞类型对液体摄取的影响将被测量，以及相应的口渴活动 追踪肠道渗透压的穹隆下器官中的神经元将在体内使用钙成像进行监测。 这些数据将揭示允许身体对摄入的食物做出适当反应的基本机制 物质和维持液体动态平衡。最终，这些实验将促进我们对 肠道的基本生理过程以及身体如何处理水和盐；这些方面的失调 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.