Central neuronal circuitry for homeostatic thermoregulation modulated by brain temperature

由脑温度调节的稳态体温调节的中枢神经元电路

• 批准号: 10709854
• 负责人: LILY Y JAN
• 金额: $ 39.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709854
• 关键词: Central; neuronal; circuitry; homeostatic; thermoregulation

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.

项目总结/摘要 维持体温在最佳水平对生存至关重要，它需要体内平衡 基于监测内部器官以及环境的温度的反馈调节。 对大脑温度变化做出反应的稳态体温调节依赖于温度- 下丘脑前部视前区（POA）的敏感神经元。这些神经元大约 内侧和外侧POA神经元的三分之一，并与温度不敏感神经元混合 控制饮水、进食、睡眠和父母行为的神经系统。自从发现了 对于大脑中的温度敏感神经元，电生理学一直是识别这些中央神经元的唯一方法。 神经元通过结合神经细胞的基因组学， 单细胞RNA-seq与全细胞膜片钳记录，我们将确定中枢神经元的上游 或这些温度敏感的POA神经元的下游，以阐明中枢神经元回路， 体温调节 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，并进一步验证这些突触连接，通过使用PGDS Cre-line驱动 图1显示了用于脑切片中光遗传学激活的温度敏感性POA神经元中的通道视紫红质表达。 为了测试视交叉上核（SCN）中的特定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-lines用于 这些SCN神经元类型驱动跨突触示踪剂表达。我们还将使用这些Cre-lines来驱动 通道视紫红质表达的SCN神经元，并记录从POA神经元，以确定他们是否 接收SCN输入以及当脑切片的温度改变时它们的发射率是否改变。 除了识别对温度敏感的上游或下游的中枢神经元外， POA神经元，这个拟议的项目包括机械研究所使用的信号的性质， 温度敏感的POA神经元，以改变其下游神经元的活动，从而调节身体 温度，以检验假设，除了经典的递质，内源性PGD 2介导 体温调节这些研究将在理解的概念层面上产生预测模型 体温调节