上海科技大学PNAS利用光遗传学等技术解析体温调节

　　

来自上海科技大学的研究人员发现了一个控制体温的下丘脑神经环路，这为进一步揭示温度调节机制提供了基础，也为深入理解中暑、发烧等生理病理反应提供了新的线索，为这些常见疾病的防治提供了新的药物靶点和治疗策略。

这一研究成果公布在《美国国家科学院院刊》（PNAS）杂志上，文章的通讯作者是上海科技大学沈伟博士，他早年毕业于清华大学，主要从事神经生物学、行为生物学的研究。

体温的稳定对于人类正常生理活动的开展十分关键。体温调节紊乱（如发热、中暑等），则会打乱很多重要生理活动，严重时甚至危及生命。体温调节主要受中枢神经系统控制。尽管人们在20世纪就已知体温的控制中枢位于下丘脑，但由于下丘脑位于大脑深部，用传统方法很难完全解析其对体温的调节机制。

为了阐明下丘脑参与体温调节的神经元与神经环路，沈伟课题组利用光遗传学、生理钙信号记录等手段，从神经环路水平对小鼠下丘脑的作用进行了系列实验，研究发现：下丘脑视前区的亚区（ventral part of lateral preoptic nucleus，vLPO）神经元调控热驱动的降温行为，而下丘脑的另一个亚区——下丘脑背中侧部的背侧（dorsomedial hypothalamic nucleus，dorsal part，DMD）的神经元负责冷刺激引起的产热机制，而且证实DMD神经元的活动受到vLPO神经元的抑制。

此外，该研究还发现一个新的热敏感神经元标记物——脑源性神经营养因子（brain-derived neurotrophic factor, BDNF），BDNF神经元代表了一类新的热调节神经元，它的发现为进一步揭示温度调节机制提供了基础。上述结果为人们深入理解中暑、发烧等生理病理反应提供了新的线索，为这些常见疾病的防治提供了新的药物靶点和治疗策略。

原文摘要：

A hypothalamic circuit that controls body temperature

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.