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.

项目概要/摘要 将体温维持在最佳水平对于生存至关重要，并且需要体内平衡 基于监测内脏器官和环境温度的反馈调节。 对大脑温度变化的反应的稳态温度调节依赖于温度- 下丘脑前部视前区（POA）的敏感神经元。这些神经元大约构成 三分之一的内侧和外侧 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。自从发现以来八十年来 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元的唯一方法 神经元。通过结合确定了第一个温度敏感 POA 神经元的分子标记 通过单细胞 RNA-seq 和全细胞膜片钳记录，我们将识别上游的中枢神经元 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，并通过使用 PGDS Cre-line 驱动进一步验证这些突触连接 通道视紫红质在温度敏感的 POA 神经元中表达，用于脑切片中的光遗传学激活。 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 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 SCN 神经元中视紫红质通道蛋白的表达，并从 POA 神经元记录以确定它们是否 接收 SCN 输入以及当大脑切片的温度改变时它们的放电率是否改变。 除了识别温度敏感上游或下游的中枢神经元之外 POA 神经元，这个拟议项目包括对 POA 神经元所使用的信号性质的机制研究 温度敏感的 POA 神经元改变其下游神经元的活动，从而调节身体 温度，以检验以下假设：除了经典递质外，内源性 PGD2 还介导 体温调节。这些研究将在概念理解层面上生成预测模型 体温调节。