Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice

Qian Zhou; Xin Fu; Jianhui Xu; Shiming Dong; Changhao Liu; Dali Cheng; Cuicui Gao; Minhua Huang; Zhiduo Liu; Xinyan Ni; Rong Hua; Hongqing Tu; Hongbin Sun; Qiwei Shen; Baoting Chen; Jin Zhang; Liye Zhang; Haitao Yang; Ji Hu; Wei Yang; Weihua Pei; Qiyuan Yao; Xing Sheng; Jie Zhang; Wen Z Yang; Wei L Shen

doi:10.1016/j.neuron.2022.11.008

Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice

Neuron. 2023 Feb 1;111(3):387-404.e8. doi: 10.1016/j.neuron.2022.11.008. Epub 2022 Dec 6.

Authors

Qian Zhou¹, Xin Fu¹, Jianhui Xu², Shiming Dong³, Changhao Liu⁴, Dali Cheng⁵, Cuicui Gao¹, Minhua Huang⁶, Zhiduo Liu⁷, Xinyan Ni⁴, Rong Hua⁸, Hongqing Tu⁴, Hongbin Sun⁴, Qiwei Shen⁸, Baoting Chen¹, Jin Zhang⁹, Liye Zhang⁴, Haitao Yang⁴, Ji Hu⁴, Wei Yang⁶, Weihua Pei¹⁰, Qiyuan Yao⁸, Xing Sheng⁵, Jie Zhang¹¹, Wen Z Yang¹², Wei L Shen¹³

Affiliations

¹ School of Life Science and Technology, Shanghai Clinical Research and Trial Center, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Thermoregulation and Inflammation Laboratory, Chengdu Medical College, Chengdu, Sichuan 610500, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), Shanghai 200031, China.
⁴ School of Life Science and Technology, Shanghai Clinical Research and Trial Center, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
⁵ Department of Electronic Engineering, Tsinghua University, Beijing 100084, China.
⁶ Department of Biophysics, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁷ University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Integrated Optoelectronics, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.
⁸ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200433, China.
⁹ School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
¹⁰ State Key Laboratory of Integrated Optoelectronics, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.
¹¹ Thermoregulation and Inflammation Laboratory, Chengdu Medical College, Chengdu, Sichuan 610500, China. Electronic address: zhangjiefa8888@126.com.
¹² School of Life Science and Technology, Shanghai Clinical Research and Trial Center, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: yangwen@shanghaitech.edu.cn.
¹³ School of Life Science and Technology, Shanghai Clinical Research and Trial Center, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: shenwei@shanghaitech.edu.cn.

PMID: 36476978
DOI: 10.1016/j.neuron.2022.11.008

Abstract

Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (T_core). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated T_core. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing T_core from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing T_core.

Keywords: TRPC4; internal sensor; preoptic area; thermoregulation; warm-sensitive neurons.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Temperature Regulation* / physiology
Body Temperature* / physiology
GABAergic Neurons
Hypothalamus
Mammals
Mice
Preoptic Area / physiology