The paraventricular thalamus is required for homeostatic sleep regulation by adenosine

  • Br J Pharmacol. 2026 Aug;183(15):4430-4447. doi: 10.1111/bph.70465.
Na Wang  1  2 ,  Yifeng Zhu  2 ,  Junya Hu  3 ,  Mengzhu Lei  4 ,  Liping Yang  2 ,  Yiran Chen  3 ,  Jiao He  4 ,  Ziliang Han  5 ,  Dongsheng Lv  5 ,  Jie Yan  2 ,  Hanxu Cai  2 ,  Fenlan Luo  2 ,  Jianxia Xia  2 ,  Chao He  2 ,  Shuancheng Ren  2 ,  Chenggang Jiang  4 ,  Yaling Wang  2 ,  Zhian Hu  1  2  3
Affiliations
  • 1. College of Bioengineering, Chongqing University, Chongqing, China.
  • 2. Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, China.
  • 3. Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China.
  • 4. Department of Sleep and Psychology, Chongqing Health Center for Women and Children, Chongqing, China.
  • 5. Sleep Medicine Center, Brain Hospital of Inner Mongolia Autonomous Region (Mental Health Center), Hohhot, China.
PMID: 42062775 DOI: 10.1111/bph.70465
Abstract

Background and purpose: Adenosine has been proposed as a prominent mediator of sleep homeostasis. Adenosine accumulation during wakefulness induces transitions to non-rapid eye movement (NREM) sleep. However, the precise neural mechanisms underlying the homeostatic regulation of sleep by adenosine have not been fully elucidated.

Experimental approach: All experiments were conducted in male mice. Genetically-encoded adenosine sensors were used to assess the dynamic fluctuations of extracellular adenosine in the paraventricular thalamus (PVT). We performed whole-cell patch-clamp recordings in vitro to investigate the effects of adenosine on PVT neurons, and combined these experiments with fibre photometry and multi-channel electrophysiological recordings in vivo. Electroencephalogram (EEG)/electromyogram (EMG) recordings were used to investigate the role of adenosine in regulating wakefulness and sleep, together with drug administration, sleep deprivation (SD) and RNA interference (RNAi).

Key results: In the PVT, extracellular adenosine was significantly elevated during wakefulness compared with NREM sleep. Adenosine caused membrane potential hyperpolarisation and decreased action potential firing in PVT neurons by activating A1 receptors (A1Rs). Adenosine also decreased spontaneous calcium activity and spike firing of PVT neurons in vivo. PVT application of adenosine promoted NREM sleep at the beginning of the dark phase, whereas A1R blockade or selective knockdown of A1Rs decreased NREM sleep mainly during the light phase. High concentrations of adenosine beyond the physiological range exhibited blunted NREM sleep-promoting effects by activating A2A receptors (A2ARs).

Conclusion and implications: These results revealed that homeostatic sleep regulation by adenosine requires the PVT, adding new insights into the homeostatic regulation of sleep.

Keywords
adenosine; adenosine A1 receptors; adenosine A2A receptors; sleep; the paraventricular thalamus.
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