Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Songjiang Research Institute, Songjiang Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Shanghai 201699, China.
Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Neuron. 2024 Apr 17;112(8):1328-1341.e4. doi: 10.1016/j.neuron.2024.01.014. Epub 2024 Feb 13.
Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.
慢性疼痛常导致睡眠障碍。然而，导致慢性疼痛患者睡眠障碍的确切神经回路机制在很大程度上仍不清楚。在这里，我们提供了令人信服的证据，证明前扣带皮层 (ACC) 中的锥体神经元 (PNs) 的过度活跃导致了神经损伤诱导的慢性疼痛小鼠模型中的失眠。在神经损伤后，ACC PNs 选择性地在失眠期间显示自发性过度活跃。然后，我们表明 ACC PNs 既是发展慢性疼痛诱导的失眠所必需的，也是足以在幼稚小鼠中模拟睡眠剥夺的。重要的是，通过光遗传学和电生理记录的结合，我们发现，ACC 投射到背内侧纹状体 (DMS) 的通路通过增强 ACC-DMS 多巴胺 D1R 神经元突触的活性和可塑性，从而导致慢性疼痛诱导的失眠。我们的研究结果揭示了 ACC PNs 在发展慢性疼痛诱导的睡眠障碍中的关键作用。
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