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

项目摘要 生命需要维持血液和间质液在一个狭窄的物理参数范围内， 血浆渗透压仅增加1-2%就刺激强烈的口渴以及激素机制， 促进肾脏的钠排泄和水潴留。这种协调反应被认为是源于 来自大脑中专门的神经元。然而，分子和细胞机制 对中枢神经系统感觉的影响仍然不清楚。最近，一个特定的群体兴奋性 由Nos 1基因表达定义的大脑穹窿下器官（SFO）内的神经元显示， 对于控制小鼠的饮酒行为是必要的和足够的，并且记录这些 清醒的行为小鼠中的神经元显示，它们被快速且剂量依赖性地激活， 血液渗透压我在这里建议系统地研究SFO神经元检测的机制， 血液渗透压的变化。我将研究这些神经元是否直接感知血液渗透压， 通过中间回路机制，并将寻求识别特定的神经或分子 这是这个过程所必需的。中枢神经感觉在神经系统疾病中起着重要的作用。 心血管健康，并在高血压，中风和心血管疾病的情况下出错。的 所提出的实验可能揭示这些病症的治疗靶点。此外，这项工作将深化 我们对调节口渴的神经回路的理解，也可能阐明更普遍的分子- 以及大脑监控身体状态的电路机制。

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.