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三叉神经脊束核-丘脑底核谷氨酸能神经环路介导小鼠慢性偏头痛

唐熘, 程颖琦, 桂韦, 张艳^*

中国科学技术大学附属第一医院(安徽省立医院)，先导医学与前沿技术研究所，神经内科，合肥 230001

摘要

慢性偏头痛(chronic migraine, CM)是一种常见且高度致残的神经系统疾病。功能性磁共振成像研究表明，异常脑区激活与慢性偏头痛存在关联，但其背后复杂的神经环路机制尚未完全阐明。三叉神经脊束核尾侧亚核(spinal trigeminalnucleus caudalis, Sp5C)是颌面部伤害性信息传入的第一级中枢，接收三叉神经的痛觉输入，并投射至丘脑等高级中枢。因此，我们探究了Sp5C脑区及其相关环路活动异常是否参与CM的发病机制。本研究通过反复腹腔注射硝酸甘油建立CM小鼠模型，并联合在体光纤记录和离体c-Fos 染色，我们发现CM小鼠出现明显的眶周和足底痛敏，同时Sp5C的谷氨酸能神经元活性显著增加。化学遗传操纵Sp5C谷氨酸能神经元能双向调控小鼠偏头痛样行为，并诱发痛情绪相关的条件性位置偏好或厌恶。通过顺行病毒示踪，我们发现丘脑底核(subthalamic nucleus, STN)存在来自Sp5C谷氨酸神经元的致密神经投射；而CM小鼠中STN脑区也被激活。光遗传激活Sp5C-STN 环路同样可使小鼠产生偏头痛样行为，并形成痛厌恶情绪记忆。综上，我们揭示了Sp5CVglut2-STN 神经环路参与CM的发生和调控。本研究为CM的中枢机制提供了新见解，并为其临床诊断和治疗提供了潜在的理论依据。

关键词： 慢性偏头痛; 三叉神经脊束核尾侧亚核; 丘脑底核; 神经环路

A glutamatergic Sp5C-STN circuit mediates chronic migraine in mice

TANG Liu, CHENG Ying-Qi, GUI Wei, ZHANG Yan^*

Department of Neurology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China

Abstract

Chronic migraine (CM) is a prevalent and highly debilitating neurological disorder. Functional magnetic resonance imaging (fMRI) studies have demonstrated associations between abnormal brain region activation and CM, yet the underlying complex neural circuitry mechanisms remain unclear. The spinal trigeminal nucleus caudalis (Sp5C) serves as the primary central hub for orofacial nociceptive input, receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus. Therefore, we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis. In this study, we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin (NTG). Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry, we found a marked periorbital and plantar mechanical allodynia in CM mice, accompanied by increased glutamatergic neuronal activity in Sp5C. Chemogenetic manipulation of Sp5C glutamatergic neurons (Sp5CVglut2) bidirectionally modulated migraine-like behaviors and induced pain-related affective states, as evidenced by conditioned place preference/aversion (CPP/CPA) paradigms. Anterograde viral tracing revealed dense projections from Sp5CVglut2 to the subthalamic nucleus (STN), which was activated in CM mice. Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice. Altogether, we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM. Our findings provide novel mechanistic insights into the central mechanisms underlying CM, establishing potential theoretical foundations for clinical diagnosis and therapeutic development.

Key words: chronic migraine; spinal trigeminal nucleus caudalis; subthalamic nucleus; neural circuit

收稿日期：　　录用日期：

通讯作者：张艳　　E-mail:

DOI: 10.13294/j.aps.2025.0112

引用本文：

唐熘, 程颖琦, 桂韦, 张艳. 三叉神经脊束核-丘脑底核谷氨酸能神经环路介导小鼠慢性偏头痛[J]. 生理学报 2026; 78 (1): 159-172.

TANG Liu, CHENG Ying-Qi, GUI Wei, ZHANG Yan. A glutamatergic Sp5C-STN circuit mediates chronic migraine in mice. Acta Physiol Sin 2026; 78 (1): 159-172