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Peer-reviewedCC BY 4.0Advanced Science

VlPAG/DRN Microglia Drive Neuropathic Pain‐Induced Depression via a Defined Neuroimmune Axis

  • Jing Yang1,2,3,4
  • Bing‐Jie Tang1,5,6
  • Jia‐Yi Li3
  • Shu‐Lan Xie1,5,6
  • Shumin Duan1,5,6
  • Junping Chen3,4
  • Shengmei Zhu1
  • Zhen‐Zhong Xu1,2,5,6
6 affiliations
  1. 1Department of Anesthesiology of First Affiliated Hospital and Liangzhu Laboratory School of Brain Science and Brain Medicine Zhejiang University School of Medicine Hangzhou China
  2. 2NANHU Brain‐Computer Interface Institute Hangzhou China
  3. 3School of Public Health Hangzhou Medical College Hangzhou Zhejiang China
  4. 4Department of Anesthesiology Ningbo No. 2 Hospital Wenzhou Medical University Ningbo China
  5. 5MOE Frontier Science Center for Brain Science and Brain‐machine Integration State Key Laboratory of Brain‐machine Intelligence Zhejiang University Hangzhou China
  6. 6NHC and CAMS Key Laboratory of Medical Neurobiology Zhejiang Key Laboratory of Pain Perception and Neuromodulation Zhejiang University Hangzhou China
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Abstract

Neuropathic pain is frequently comorbid with anxiety and depression, yet the mechanisms linking immune signaling to affective brain circuits remain poorly understood. Here, we identify a neuroimmune circuit in which peripheral nerve injury activates microglia in the midbrain ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DRN), triggering an NLRP3–IL‐1β‐dependent inflammatory cascade. Direct optogenetic or chemogenetic activation of vlPAG/DRN microglia is sufficient to drive negative affective behaviors. We show that local VGLUT2+ glutamatergic neurons (vlPAG/DRNGlu) are the principal IL‐1R1–expressing targets; IL‐1β activates these neurons to drive anxiety‐ and depression‐like states. Conversely, microglia‐specific Nlrp3 deletion or local IL‐1R1 blockade prevents neuropathic pain–induced affective deficits. Furthermore, circuit mapping and functional manipulation reveal an excitatory vlPAG/DRNGlu to the bed nucleus of the stria terminalis (BNSTGABA) pathway that is both sufficient to induce and required to maintain the affective component of neuropathic pain. Together, our findings delineate a microglia–vlPAG/DRNGlu–BNSTGABA axis that translates peripheral injury into maladaptive emotional states, revealing a discrete neuroimmune circuit substrate for mood comorbidity in chronic pain.

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Cite

BibTeXRIS
BibTeX
@article{yang2026vlpagdrn,
  title = {{VlPAG/DRN Microglia Drive Neuropathic Pain‐Induced Depression via a Defined Neuroimmune Axis}},
  author = {Jing Yang and Bing‐Jie Tang and Jia‐Yi Li and Shu‐Lan Xie and Shumin Duan and Junping Chen and Shengmei Zhu and Zhen‐Zhong Xu},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.77071},
  url = {https://doi.org/10.1002/advs.77071},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - VlPAG/DRN Microglia Drive Neuropathic Pain‐Induced Depression via a Defined Neuroimmune Axis
AU  - Jing Yang
AU  - Bing‐Jie Tang
AU  - Jia‐Yi Li
AU  - Shu‐Lan Xie
AU  - Shumin Duan
AU  - Junping Chen
AU  - Shengmei Zhu
AU  - Zhen‐Zhong Xu
PY  - 2026
DA  - 2026/08/11
JO  - Advanced Science
DO  - 10.1002/advs.77071
UR  - https://doi.org/10.1002/advs.77071
AB  - Neuropathic pain is frequently comorbid with anxiety and depression, yet the mechanisms linking immune signaling to affective brain circuits remain poorly understood. Here, we identify a neuroimmune circuit in which peripheral nerve injury activates microglia in the midbrain ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DRN), triggering an NLRP3–IL‐1β‐dependent inflammatory cascade. Direct optogenetic or chemogenetic activation of vlPAG/DRN microglia is sufficient to drive negative affective behaviors. We show that local VGLUT2+ glutamatergic neurons (vlPAG/DRNGlu) are the principal IL‐1R1–expressing targets; IL‐1β activates these neurons to drive anxiety‐ and depression‐like states. Conversely, microglia‐specific Nlrp3 deletion or local IL‐1R1 blockade prevents neuropathic pain–induced affective deficits. Furthermore, circuit mapping and functional manipulation reveal an excitatory vlPAG/DRNGlu to the bed nucleus of the stria terminalis (BNSTGABA) pathway that is both sufficient to induce and required to maintain the affective component of neuropathic pain. Together, our findings delineate a microglia–vlPAG/DRNGlu–BNSTGABA axis that translates peripheral injury into maladaptive emotional states, revealing a discrete neuroimmune circuit substrate for mood comorbidity in chronic pain.
SN  - 2198-3844
ER  -