“脑干-下丘脑”体温调节神经环路的解析

Adult mammals precisely maintain core body temperature (Tcore) within a narrow range. Maintenance of Tcore orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges, which mainly depends on the thermoregulatory system in the central nervous system. The system is essential for survival because a slight deviation of Tcore can adversely affect cellular metabolism, causing many diseases such as fever, heatstroke and obesity. Therefore, decoding the neural circuit of thermoregulation not only helps to deepen people's understanding of energy homeostatic, but also provides a scientific basis for the prevention and treatment of thermoregulation disorders. Previous study have shown that the preoptic area (POA) of the hypothalamus plays an important role in maintaining a stable Tcore. In the proposal, we proposed that 1) The lateral parabrachial nucleus (LPB) → POA pathway is activated by heat stimuli, and then promotes heat dissipation and reduces body temperature. 2) LPB → the dorsal part of the dorsomedial hypothalamus (DMD) pathway is activated by cold stimuli, and then promotes heat production and increases body temperature. 3) There is an antagonism between POA and DMD neurons. We will test our hypothesis using advanced methodology such as opotogenetic, fiber photometry, electrophysiological recordings, single cell reverse transcription PCR and phosphoTRAP (ribosome affinity purification) mRNA sequencing. Besides, we will link the neural circuits of thermoregulation system to obesity, hoping to clarify the neural mechanism of thermoregulation and find new factors for anti-obesity drug development.

温度影响生物体各种生理过程，机体消耗近~50%能量将体温维持在一个狭窄范围内。体温调节依赖于中枢神经系统复杂精细的神经环路调节体内能量代谢水平而实现，当温度调节系统发生紊乱时，会引起发烧、中暑并可能加重肥胖等疾病。因此，阐明体温调节的机制，不仅有助于深化理解自身稳态功能，也有助于体温调节紊乱引发的疾病的预防和处理，为新药开发提供科学依据。传统观点认为，视前区（POA）接受温度刺激信号引发散热或产热行为维持体温。本研究中，我们根据之前的研究成果和初步实验数据提出：当冷热信号传至外侧臂旁核（LPB）时，分别激活POA和背内侧核背侧（DMD），进而分别引起散热和产热行为；另外，POA与DMD相互拮抗，使得产热或者散热反应的效果最大化。我们将结合光遗传学、光纤记录和电生理等手段验证上述假设，进一步完善温度调节神经环路，并在此基础上研究温度调节环路对产热和体重的影响，为新的抗肥胖策略提供科学基础。

当机体受到外界环境温度或药物等刺激时，哺乳动物将调节自身代谢行为或生理学反应（饮食、活动等）将体温维持在一个狭窄范围，即体温调节。体温调节主要依赖于中枢神经系统中复杂而精细的神经环路来实现。阐明体温调节的机制，不仅有助于深化人们对能量稳态功能的理解，也有助于发烧等体温相关疾病和肥胖等代谢疾病的预防和处理，为新药的开发提供理论基础。本项目中，我们发现：1）高温刺激下，脑干外侧臂旁核（LPB）投射向下丘脑视前区（POA）的强啡肽原（Pdyn）神经元被显著激活；2）脑干LPB的胆囊收缩素（CCK）神经元可以被冷刺激激活，升高小鼠体温；3）下丘脑背内侧（DMH）的脑源性营养因子（BDNF）也可以被冷刺激激活，同时阻断这类神经元的递质释放，引起小鼠脂肪含量和体重的显著增加。我们的工作进一步完善了温度调节神经环路，为发烧等提供了潜在的治疗靶点。同时，我们初步建立了温度调节与肥胖之间的直接联系，为防治肥胖提供了新的策略。