Hyperexcitable VTA-mPFC dopaminergic circuit disrupts sleep spindle and mediates sleep fragmentation after chronic social defeat stress

  • Neuron. 2026 May 19:S0896-6273(26)00332-6. doi: 10.1016/j.neuron.2026.04.037.
Rui Li  1 ,  Xinxin Zhang  1 ,  Jiannan Li  1 ,  Huiming Li  1 ,  Rui Wang  2 ,  Rou Xue  1 ,  Hui Wang  1 ,  Dan Wang  1 ,  Lei Liu  1 ,  Xiao Yu  3 ,  Min Cai  4 ,  Jinghao Wang  1 ,  Zhixin Wu  1 ,  Qianzi Yang  5 ,  Ao Li  6 ,  Qun Wang  1 ,  Tingting Gu  1 ,  Sa Wang  1 ,  Guangchao Zhao  7 ,  Hailong Dong  8
Affiliations
  • 1. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Key Laboratory of Anesthesiology, Ministry of Education, Shaanxi Provincial Clinical Research Center for Anesthesiology Medicine, Xi'an 710032, China.
  • 2. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Key Laboratory of Anesthesiology, Ministry of Education, Shaanxi Provincial Clinical Research Center for Anesthesiology Medicine, Xi'an 710032, China; Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • 3. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 4. Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
  • 5. Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
  • 6. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Key Laboratory of Anesthesiology, Ministry of Education, Shaanxi Provincial Clinical Research Center for Anesthesiology Medicine, Xi'an 710032, China; Department of Anesthesiology, The First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China.
  • 7. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Key Laboratory of Anesthesiology, Ministry of Education, Shaanxi Provincial Clinical Research Center for Anesthesiology Medicine, Xi'an 710032, China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, Xi'an 710032, China. Electronic address: [email protected].
  • 8. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Key Laboratory of Anesthesiology, Ministry of Education, Shaanxi Provincial Clinical Research Center for Anesthesiology Medicine, Xi'an 710032, China. Electronic address: [email protected].
PMID: 42161276 DOI: 10.1016/j.neuron.2026.04.037
Abstract

Chronic stress disrupts sleep maintenance, yet its neural basis remains unclear. Here, we demonstrated that mice subjected to chronic social defeat stress exhibit fragmented non-rapid eye movement sleep (NREMs), accompanied by reduced density and quality of sleep spindles. Chronic stress enhances the firing and burst activity of ventral tegmental area dopaminergic (VTADA) neurons, leading to excessive dopamine release in the medial prefrontal cortex (mPFC). This dopaminergic surge disrupts the continuity of electroencephalogram (EEG) spindles, thereby disturbing the stability of NREMs. Blocking dopamine signaling along the VTA-mPFC pathway during stress exposure or pharmacologically inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated Ih currents of VTA neurons after chronic stress attenuated sleep fragmentation and restored normal spindle metrics. Our study identifies aberrant VTADA burst firing as a critical circuit-level contributor to stress-induced sleep disturbance and proposes a potential mechanistic entry point for dissecting dopamine-dependent regulation of NREMs stability.

Keywords
HCN channel; VTA dopamine; chronic stress; firing pattern; sleep disturbance; sleep spindle.
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