Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis PMID: 42321470

ADC Targets in Oncology

2026-04-10

Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis

Nat Neurosci. 2026 Jun 19. doi: 10.1038/s41593-026-02332-x.

Huateng Cao ¹ ² , Kui Wang ¹ , Jin Zhao ¹ ³ , Zhong-Hua Zha ⁴ ⁵ , Qian Zhang ¹ , Yijin Xiu ¹ ³ , Bangsheng Wu ⁶ , Shajin Huang ¹ , Xiao-Na Zhu ⁷ , Xiaoting Li ⁴ , Jianan Chen ⁸ , Han Wen ⁹ , Siwen Pan ¹ ³ , Ke-Xin Yang ⁵ , Ji Hu ⁵ , Jin-Tai Yu ⁶ , Zhi-Jie Liu ⁴ ⁵ , Tian Hua ⁴ ⁵ , Yu Mu ¹⁰ , Zhian Hu ¹¹ ¹² , Peng Yuan ¹³ , Zhe Zhang ¹⁴

Affiliations

1. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
2. Yiwu Research Institute of Fudan University, Yiwu, China.
3. University of Chinese Academy of Sciences, Beijing, China.
4. iHuman Institute, ShanghaiTech University, Shanghai, China.
5. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
6. Department of Neurology and National Center for Neurological Diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
7. Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine and School of Psychology, Shanghai, China.
8. DP Technology, Beijing, China.
9. AI for Science Institute, Beijing, China.
10. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. [email protected].
11. Department of Physiology, Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China. [email protected].
12. Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China. [email protected].
13. Department of Rehabilitation Medicine, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, China. [email protected].
14. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. [email protected].

Abstract

Wakefulness produces sleep-promoting substances and the cerebrospinal fluid contains substances that reflect homeostatic sleep pressure. However, identities of such molecules, and the neural mechanisms for producing and sensing them, remain mysterious. Here we show that cerebrospinal fluid levels of tryptamine (TRPA) track homeostatic sleep pressure in nocturnal mice and diurnal pigs, reflecting physical activity history independently of light-dark cycles. We developed a ratiometric fluorescent sensor for TRPA and showed that TRPA is produced by wake-active monoaminergic nuclei in the diencephalon and brainstem and is secreted in an activity-dependent manner. We showed that released TRPA binds to G-protein-coupled receptor 139 (GPR139) and enhances neuronal excitability in the hypothalamic preoptic area to promote sleep. TrpA-GPR139 signaling was necessary for homeostatic sleep rebound and small-molecule GPR139 agonists promoted sleep duration and quality. Together, our study reveals TRPA as a signal related to sleep homeostasis and GPR139 as a druggable target against its disruption.