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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

Received: 　　Accepted:

Corresponding author: 张艳　　E-mail:

DOI: 10.13294/j.aps.2025.0112

Citing This Article：

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