Bao Shu-Ting, Rao Fang, Yin Cui, Niu Yong, Cao Jun-Li, Xiao Cheng, Zhou Chunyi
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
PLoS Biol. 2025 May 20;23(5):e3003170. doi: 10.1371/journal.pbio.3003170. eCollection 2025 May.
The medial prefrontal cortex (mPFC) is implicated in emotional processing, cognition, and pain sensation, moreover, its circuitry undergoes neuroplastic changes in chronic pain. Although the nucleus reuniens (RE) of the thalamus provides significant glutamatergic inputs to the mPFC, it remains unclear whether this projection contributes to plasticity changes in the mPFC and pain-related behaviors in chronic pain. Using fiber photometry, we demonstrated that RE neurons responded to pain stimulation and emotional changes. Optogenetic activation of RE neurons and their projections to the mPFC (RE-mPFC projection) elicits hyperalgesia and depression-like behaviors in naïve mice. In a neuropathic pain mouse model, RE neurons were hyperactive, and the RE-mPFC projection was enhanced with a marked preference for the part innervating GABAergic circuits in the mPFC to that controlling mPFC neurons projecting to the ventrolateral periaqueductal gray (vlPAG). Expectedly, optogenetic inhibition of RE neurons and the RE-mPFC projection ameliorated pain-like and depression-like behaviors in neuropathic pain mice. Additionally, chemogenetic inhibition of RE-mPFC neurons conferred analgesia in neuropathic pain mice exposed to both acute and chronic morphine. Our findings highlight the significant role of the RE-mPFC pathway in neuropathic pain comorbid with depression, suggesting its potential as a target for treatment of neuropathic pain.
内侧前额叶皮质（mPFC）参与情绪处理、认知和痛觉感受，此外，其神经回路在慢性疼痛中会发生神经可塑性变化。虽然丘脑 reunions 核（RE）向 mPFC 提供大量谷氨酸能输入，但尚不清楚该投射是否有助于 mPFC 的可塑性变化以及慢性疼痛中与疼痛相关的行为。使用光纤光度法，我们证明 RE 神经元对疼痛刺激和情绪变化有反应。对 RE 神经元及其向 mPFC 的投射（RE-mPFC 投射）进行光遗传学激活会在未处理的小鼠中引发痛觉过敏和抑郁样行为。在神经性疼痛小鼠模型中，RE 神经元过度活跃，且 RE-mPFC 投射增强，对 mPFC 中支配 GABA 能回路的部分的偏好明显高于控制投射到腹外侧导水管周围灰质（vlPAG）的 mPFC 神经元的部分。不出所料，对 RE 神经元和 RE-mPFC 投射进行光遗传学抑制可改善神经性疼痛小鼠的疼痛样和抑郁样行为。此外，对 RE-mPFC 神经元进行化学遗传学抑制可使暴露于急性和慢性吗啡的神经性疼痛小鼠产生镇痛作用。我们的研究结果突出了 RE-mPFC 通路在与抑郁症共病的神经性疼痛中的重要作用，表明其作为神经性疼痛治疗靶点的潜力。
