Central neuronal circuitry for homeostatic thermoregulation modulated by brain temperature

项目摘要/摘要 将体温维持在最佳水平是生存的关键，这需要体内平衡 反馈调节建立在监测内脏温度和环境的基础上。 响应大脑温度变化的动态平衡体温调节依赖于温度- 下丘脑前区(POA)的敏感神经元。这些神经元组成了大约 1/3的内侧和外侧POA神经元与温度不敏感神经元混合在一起 控制饮酒、进食、睡眠和父母行为的法律。自发现以来的八十年 大脑中对温度敏感的神经元，电生理学一直是识别这些中枢神经系统的唯一方法 神经元。通过结合结合确定了第一个温度敏感型POA神经元的分子标记 用全细胞膜片钳记录单细胞rna-seq，我们将识别位于上游的中枢神经元。 或这些温度敏感型POA神经元的下游，以阐明中枢神经元回路 温度调节。 为了识别从温度敏感的POA神经元接收输入的中枢神经元，我们将使用 跨突触示踪剂，并通过使用PGDS CRE-line驱动进一步验证这些突触连接 脑片光发生激活温度敏感型视紫红质神经元的通道视紫红质表达。 为了测试视交叉上核(SCN)中特定的神经元类型是否支配温度- 敏感的POA神经元来调节体温的昼夜变化，我们将使用Cre-line来 这些SCN神经元类型驱动跨突触示踪剂的表达。我们还将使用这些CRE线路来驾驶 通道视紫红质在SCN神经元中的表达，并从POA神经元记录以确定它们是否 接受SCN输入，以及当脑片温度改变时，它们的放电率是否改变。 除了识别温度敏感区上游或下游的中枢神经元 POA神经元，这项拟议的项目包括对 温度敏感型POA神经元改变其下游神经元的活动以调节身体 温度，以检验这一假设，除了经典的递质，内源性PGD2介导 温度调节。这些研究将在概念理解的水平上生成预测性模型 温度调节。

Project Summary/Abstract Maintenance of body temperature at the optimal level is crucial for survival, and it requires homeostatic feedback regulation based on monitoring the temperature of internal organs as well as the environment. Homeostatic thermoregulation in response to changes of brain temperature relies on the temperature- sensitive neurons in the preoptic area of the anterior hypothalamus (POA). These neurons constitute about one third of the medial and lateral POA neurons and are intermingled with temperature-insensitive neurons that control drinking, feeding, sleep, and parental behaviors. For eight decades since the discovery of temperature-sensitive neurons in the brain, electrophysiology has been the only way to identify these central neurons. Having identified the first molecular marker for temperature-sensitive POA neurons by combining single-cell RNA-seq with whole-cell patch-clamp recording, we will identify central neurons that are upstream or downstream of these temperature-sensitive POA neurons, to elucidate the central neuronal circuitry for thermoregulation. To identify central neurons that receive input from temperature-sensitive POA neurons, we will use trans-synaptic tracers, and further verify these synaptic connections by using the PGDS Cre-line to drive channelrhodopsin expression in temperature-sensitive POA neurons for optogenetic activation in brain slices. To test whether specific neuronal types in the suprachiasmatic nucleus (SCN) innervate temperature- sensitive POA neurons to modulate the circadian variation of body temperature, we will use Cre-lines for these SCN neuronal types to drive trans-synaptic tracer expression. We will also use these Cre-lines to drive channelrhodopsin expression in SCN neurons, and record from POA neurons to determine whether they receive SCN input and whether their firing rate changes when the temperature of the brain slice is altered. In addition to identifying central neurons that are upstream or downstream of temperature-sensitive POA neurons, this proposed project includes mechanistic studies on the nature of the signals used by temperature-sensitive POA neurons to alter the activity of their downstream neurons so as to modulate body temperature, to test the hypothesis that, besides classical transmitters, endogenous PGD2 mediates thermoregulation. These studies will generate predictive models at a conceptual level of understanding thermoregulation.