Xie Guoguang, Liu Yiqiong, Qi Xuetao, Bhattacherjee Aritra, Zhang Chao, Zhang Yi
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
bioRxiv. 2025 Aug 25:2025.08.22.671771. doi: 10.1101/2025.08.22.671771.
Both the medial prefrontal cortex (mPFC) and thalamus have been implicated in pain regulation. However, the roles of the mPFC-thalamus connection in pain and how the mPFC modulates nociceptive processing within the brain remain unclear. Here, we show that the mPFC neurons that project to thalamus are marked by expression and deactivated in both acute and chronic pain. Persistent inactivation of the mPFC neurons enhances nociceptive sensitivity, while their activation alleviates multiple aspects of pain. Circuit-specific manipulations revealed that the projections to parataenial nucleus, mediodorsal and ventromedial thalamus differentially modulate sensory and affective pain. Additionally, the mPFC neurons receive cholinergic input from the basal forebrain, particularly the horizonal diagonal band (HDB). Notably, activation of the α4β2-containing nicotinic acetylcholine receptor in mPFC exerts antinociceptive effects in neuron-dependent manner. Together, our study defines an HDB→mPFC →thalamus circuit essential for sensory and affective pain modulation and underscores the therapeutic potential of targeting mPFC cholinergic signaling in chronic pain management.
内侧前额叶皮质（mPFC）和丘脑均与疼痛调节有关。然而，mPFC与丘脑之间的连接在疼痛中的作用以及mPFC如何调节大脑内的伤害性处理仍不清楚。在这里，我们表明投射到丘脑的mPFC神经元以特定表达为特征，并且在急性和慢性疼痛中均被失活。mPFC神经元的持续失活会增强伤害性敏感性，而激活它们则可减轻疼痛的多个方面。特定回路的操作表明，投射到旁束核、背内侧和腹内侧丘脑的神经元对感觉性疼痛和情感性疼痛有不同的调节作用。此外，mPFC神经元接受来自基底前脑，特别是水平对角带（HDB）的胆碱能输入。值得注意的是，mPFC中含α4β2的烟碱型乙酰胆碱受体的激活以神经元依赖的方式发挥抗伤害感受作用。总之，我们的研究定义了一个对感觉性疼痛和情感性疼痛调节至关重要的HDB→mPFC→丘脑回路，并强调了在慢性疼痛管理中靶向mPFC胆碱能信号传导的治疗潜力。
