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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
1Department of Anesthesiology of First Affiliated Hospital, and Liangzhu Laboratory, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
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.
Insights
Peripheral nerve injury activates midbrain microglia, initiating an inflammatory cascade that drives anxiety and depression. This neuroimmune circuit translates pain into emotional distress, offering targets for treating chronic pain comorbidities.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Neuropathic pain often co-occurs with anxiety and depression.
- The neuroimmune mechanisms linking pain to affective disorders are not well understood.
Purpose of the Study:
- To identify the neuroimmune circuit linking peripheral nerve injury to affective behaviors.
- To elucidate the role of microglia and specific inflammatory mediators in pain-related mood disorders.
Main Methods:
- Investigated microglia activation in the midbrain ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DRN) following nerve injury.
- Utilized optogenetic and chemogenetic techniques to manipulate microglia and neuronal activity.
- Examined the role of NLRP3 inflammasome, IL-1β, and IL-1R1 signaling.
- Mapped neuronal pathways using circuit tracing and functional manipulation.
Main Results:
- Peripheral nerve injury activates vlPAG/DRN microglia, initiating an NLRP3-IL-1β cascade.
- Activation of vlPAG/DRN microglia directly induces negative affective behaviors.
- IL-1β targets VGLUT2+ glutamatergic neurons (vlPAG/DRNGlu), driving anxiety and depression.
- Microglia-specific Nlrp3 deletion or IL-1R1 blockade prevents pain-induced affective deficits.
- An excitatory vlPAG/DRNGlu to BNSTGABA pathway mediates the affective component of neuropathic pain.
Conclusions:
- A novel neuroimmune circuit involving microglia, vlPAG/DRNGlu neurons, and BNSTGABA neurons underlies the affective comorbidities of neuropathic pain.
- This microglia-vlPAG/DRNGlu-BNSTGABA axis translates peripheral injury signals into maladaptive emotional states.
- Targeting this circuit offers potential therapeutic strategies for chronic pain and associated mood disorders.