Morrison Shaun F, Cano Georgina, Hernan Shelby L, Chiavetta Pierfrancesco, Tupone Domenico
Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Curr Biol. 2025 Jan 6;35(1):59-76.e4. doi: 10.1016/j.cub.2024.11.006. Epub 2024 Dec 2.
To maintain core body temperature in mammals, CNS thermoregulatory networks respond to cold exposure by increasing brown adipose tissue and shivering thermogenesis. However, in hibernation or torpor, this canonical thermoregulatory response is replaced by a new, emerging paradigm, thermoregulatory inversion (TI), an alternative homeostatic state in which cold exposure inhibits thermogenesis and warm exposure stimulates thermogenesis. Here, we demonstrate that in the non-torpid rat, either exclusion of the canonical thermoregulatory integrator in the preoptic hypothalamus or inhibition of neurons in the ventromedial periventricular area (VMPeA) induces the TI state through an alternative thermoregulatory pathway. Within this pathway, we have identified a dynorphinergic input to the dorsomedial hypothalamus from the dorsolateral parabrachial nucleus that plays a critical role in mediating the cold-evoked inhibition of thermogenesis during TI. Our results reveal a novel thermosensory reflex circuit within the mammalian CNS thermoregulatory pathways and support the potential for pharmacologically inducing the TI state to elicit therapeutic hypothermia in non-hibernating species, including humans.
为维持哺乳动物的核心体温，中枢神经系统（CNS）的体温调节网络会通过增加棕色脂肪组织和颤抖产热来应对冷暴露。然而，在冬眠或蛰伏状态下，这种典型的体温调节反应被一种新出现的模式——体温调节反转（TI）所取代，TI是一种替代性的稳态状态，其中冷暴露会抑制产热，而热暴露会刺激产热。在此，我们证明，在非蛰伏的大鼠中，视前下丘脑典型体温调节整合器的缺失或室周腹内侧区（VMPeA）神经元的抑制会通过一条替代性体温调节途径诱导TI状态。在这条途径中，我们确定了从背外侧臂旁核到下丘脑背内侧核的强啡肽能输入，它在介导TI期间冷诱发的产热抑制中起关键作用。我们的结果揭示了哺乳动物CNS体温调节途径内一种新的热感觉反射回路，并支持通过药理学诱导TI状态以在包括人类在内的非冬眠物种中引发治疗性低温的可能性。
