Liu Yue-Ying, Wu Ke, Dong Yu-Ting, Jia Ru, Chen Xing-Han, Ge An-Yu, Cao Jun-Li, Zhang Yong-Mei
NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, China.
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
Neuropsychopharmacology. 2025 Jun;50(7):1039-1050. doi: 10.1038/s41386-025-02084-5. Epub 2025 Mar 15.
Neuropathic pain, which has become a major public health concern, is frequently accompanied by the deterioration of affective behavior and cognitive function. However, the brain circuitry underlying these changes is poorly understood. Therefore, we aimed to identify in a mouse model the converging circuit that influences the sensory, affective, and cognitive consequences of neuropathic pain. The lateral habenula (LHb) and ventral tegmental area (VTA) have been confirmed to play critical roles in the regulation of pain, cognition, and depression. Given the essential role of the LHb in depression and cognition, we attempted to clarify how neural circuitry involving the LHb integrates pain-related information. Our data confirmed that the VTA receives projections from the LHb, but our results suggest that inhibition of this direct pathway has no effect on the behavior of mice with chronic neuropathic pain. The rostromedial tegmental nucleus (RMTg), a GABAergic structure believed to underlie the transient inhibition of DAergic neurons in the VTA, received glutamatergic inputs from the LHb and projected strongly to the VTA. Furthermore, our data suggest that a projection from LHb glutamatergic neurons to RMTg GABAergic neurons in the VTA, constituting an indirect LHb → RMTg → VTA pathway, participates in peripheral nerve injury-induced nociceptive hypersensitivity, depressive-like behavior, and cognitive dysfunction. Ex vivo extracellular recordings of LHb neurons showed that the proportion of burst-firing cells in the LHb was significantly increased in indirect projections rather than in direct projections. This may explain the functional discrepancies between direct and indirect projections of the LHb to the VTA. Collectively, our study identifies a pivotal role of the LHb → RMTg → VTA pathway in processing pain. This pathway may offer new therapeutic targets to treat neuropathic pain and its associated depressive-like and cognitive impairments.
神经性疼痛已成为一个主要的公共卫生问题，常伴有情感行为和认知功能的恶化。然而，这些变化背后的脑回路却鲜为人知。因此，我们旨在在小鼠模型中确定影响神经性疼痛的感觉、情感和认知后果的汇聚回路。外侧缰核（LHb）和腹侧被盖区（VTA）已被证实在疼痛、认知和抑郁的调节中起关键作用。鉴于LHb在抑郁和认知中的重要作用，我们试图阐明涉及LHb的神经回路如何整合疼痛相关信息。我们的数据证实VTA接受来自LHb的投射，但我们的结果表明抑制这条直接通路对慢性神经性疼痛小鼠的行为没有影响。吻内侧被盖核（RMTg）是一个GABA能结构，被认为是VTA中多巴胺能神经元瞬时抑制的基础，它接受来自LHb的谷氨酸能输入并强烈投射到VTA。此外，我们的数据表明，从LHb谷氨酸能神经元到VTA中RMTg GABA能神经元的投射，构成了一条间接的LHb→RMTg→VTA通路，参与了外周神经损伤诱导的伤害性超敏反应、抑郁样行为和认知功能障碍。对LHb神经元的离体胞外记录显示，在间接投射中，LHb中爆发式放电细胞的比例显著增加，而在直接投射中则不然。这可能解释了LHb到VTA的直接和间接投射之间的功能差异。总的来说，我们的研究确定了LHb→RMTg→VTA通路在处理疼痛中的关键作用。这条通路可能为治疗神经性疼痛及其相关的抑郁样和认知障碍提供新的治疗靶点。
