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Purpose <p>Post-operative sleep disturbance affects more than 60% of surgical patients and&#xa0;impedes recovery.&#xa0;Although general anesthesia itself may profoundly remodel brain function and contribute to this pathology, the underlying neural mechanisms remain unclear. We previously identified the dorsomedial hypothalamus (DMH) as a key modulator of emergence and&#xa0;arousal. Here, we investigated the distinct roles of DMH glutamatergic&#xa0;neurons (DMH<sup>Glu</sup>) and GABAergic neurons&#xa0;(DMH<sup>GABA</sup>) in the pathophysiology of post-anesthesia sleep disturbance (PSD).</p> Methods <p>Using a mouse model of PSD induced by 2 h of 1.4% isoflurane anesthesia, we used chemogenetics to selectively activate or inhibit DMH neurons. Sleep–wake architecture was assessed using wireless electroencephalography (EEG) and electromyography (EMG) biotelemetry, complemented by fiber photometry for neuronal activity monitoring and single-nucleus RNA sequencing for molecular profiling.</p> Results <p>Isoflurane anesthesia induced a delayed-onset sleep disturbance characterized by increased wakefulness and reduced, fragmented sleep during the subsequent rest phase. Notably, DMH<sup>Glu</sup> neurons showed heightened activity specifically during rest-phase wakefulness, whereas DMH<sup>GABA</sup> neurons were predominantly active during wakefulness and non-rapid eye movement sleep in the post-anesthesia active phase. Activation of DMH<sup>Glu</sup> neurons reversed PSD in a circadian phase-dependent manner, while both activation and inhibition of DMH<sup>GABA</sup> neurons improved PSD without significant phase variation. Single-nucleus RNA sequencing revealed the involvement of retrograde endocannabinoid signaling in both DMH<sup>Glu</sup> and DMH<sup>GABA</sup> neurons. Administration of a type 1 cannabinoid receptor (CB1R) antagonist alleviated PSD, potentially by disinhibiting DMH<sup>Glu</sup> neurons and remodeling the integration of excitatory and inhibitory inputs onto DMH<sup>GABA</sup> neurons.</p> Conclusions <p>DMH<sup>Glu</sup> and DMH<sup>GABA</sup> neurons differentially regulate PSD through distinct, CB1R-mediated presynaptic modulation, providing novel mechanistic insights into PSD and identifying potential therapeutic targets for its treatment.</p>

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DMH glutamatergic and GABAergic neurons differentially regulate post-anesthesia sleep disturbance through CB1R signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Jiajia Wang,
  • Fang Zhou,
  • Xinxin Zhang,
  • Sansan Jia,
  • Huiqing Liu,
  • Xiaofei Fei,
  • Lu Yin,
  • Zefei Zhang,
  • Yang Liu,
  • Yuan Fang,
  • Hailong Dong,
  • Zhihong Lu,
  • Haixing Zhong

摘要

Purpose

Post-operative sleep disturbance affects more than 60% of surgical patients and impedes recovery. Although general anesthesia itself may profoundly remodel brain function and contribute to this pathology, the underlying neural mechanisms remain unclear. We previously identified the dorsomedial hypothalamus (DMH) as a key modulator of emergence and arousal. Here, we investigated the distinct roles of DMH glutamatergic neurons (DMHGlu) and GABAergic neurons (DMHGABA) in the pathophysiology of post-anesthesia sleep disturbance (PSD).

Methods

Using a mouse model of PSD induced by 2 h of 1.4% isoflurane anesthesia, we used chemogenetics to selectively activate or inhibit DMH neurons. Sleep–wake architecture was assessed using wireless electroencephalography (EEG) and electromyography (EMG) biotelemetry, complemented by fiber photometry for neuronal activity monitoring and single-nucleus RNA sequencing for molecular profiling.

Results

Isoflurane anesthesia induced a delayed-onset sleep disturbance characterized by increased wakefulness and reduced, fragmented sleep during the subsequent rest phase. Notably, DMHGlu neurons showed heightened activity specifically during rest-phase wakefulness, whereas DMHGABA neurons were predominantly active during wakefulness and non-rapid eye movement sleep in the post-anesthesia active phase. Activation of DMHGlu neurons reversed PSD in a circadian phase-dependent manner, while both activation and inhibition of DMHGABA neurons improved PSD without significant phase variation. Single-nucleus RNA sequencing revealed the involvement of retrograde endocannabinoid signaling in both DMHGlu and DMHGABA neurons. Administration of a type 1 cannabinoid receptor (CB1R) antagonist alleviated PSD, potentially by disinhibiting DMHGlu neurons and remodeling the integration of excitatory and inhibitory inputs onto DMHGABA neurons.

Conclusions

DMHGlu and DMHGABA neurons differentially regulate PSD through distinct, CB1R-mediated presynaptic modulation, providing novel mechanistic insights into PSD and identifying potential therapeutic targets for its treatment.