Cell-type-specific investigation of the mechanisms underlying neural osmosensation

项目总结 生命需要在很小的物理参数范围内维持血液和间质液体，并且 血浆渗透压只增加1-2%会刺激强烈的口渴以及激素机制， 促进肾脏的钠排泄和水分保持。这种协调的反应被认为起源于 来自大脑中特殊的渗透敏感神经元。然而，分子和细胞机制 对中枢渗透感觉的责任仍然没有明确的定义。最近，一群特定人群的兴奋性 大脑穹隆下器(SFO)内由NOS1基因表达定义的神经元被证明是 对于控制小鼠的饮酒行为是必要的和充分的，并记录这些活动 清醒的、行为正常的小鼠的神经元显示，它们迅速地被剂量依赖性地通过增加激活 在血液渗透压方面。我建议在这里系统地研究SFO神经元检测到 血液渗透压的变化。我将检查这些神经元是直接感觉到血液渗透压，还是 通过中间电路机制，将寻求识别特定的神经或分子 此过程所需的组件。中枢性渗透感觉在 心血管健康，在高血压、中风和心血管疾病的情况下会出错。这个 拟议中的实验可能会揭示此类疾病的治疗目标。此外，这项工作将深化 我们对调节口渴的神经回路的理解也可能阐明更一般的分子-- 以及大脑监测身体状态的回路机制。

Project summary Life requires maintenance of the blood and interstitial fluids within a narrow range of physical parameters, and an increase in plasma osmolarity of only 1-2% stimulates intense thirst as well as hormonal mechanisms that promote sodium excretion and water retention by the kidney. This coordinated response is thought to originate from specialized osmosensitive neurons in the brain. However, the molecular and cellular mechanisms responsible for central osmosensation remain poorly defined. Recently, a specific population of excitatory neurons within the subfornical organ (SFO) of the brain defined by expression of the gene Nos1 was shown to be necessary and sufficient for the control of drinking behavior in mice, and recordings of the activity of these neurons in awake, behaving mice revealed that they are rapidly and dose-dependently activated by increases in blood osmolarity. I propose here to systematically investigate the mechanism by which SFO neurons detect changes in the blood osmolarity. I will examine whether these neurons sense blood osmolarity directly or through an intermediary circuit mechanism and will seek to identify the specific neural or molecular components that are necessary for this process. Central osmosensation plays an important role in cardiovascular fitness, and goes awry in cases of hypertension, stroke, and cardiovascular disease. The proposed experiments may reveal therapeutic targets for such conditions. Additionally, this work will deepen our understanding of the neural circuit that regulates thirst and may also illuminate more general molecular- and circuit-mechanisms by which the brain monitors the state of the body.