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

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/DRN Glu ) 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/DRN Glu to the bed nucleus of the stria terminalis (BNST GABA ) pathway that is both sufficient to induce and required to maintain the affective component of neuropathic pain. Together, our findings delineate a microglia–vlPAG/DRN Glu –BNST GABA axis that translates peripheral injury into maladaptive emotional states, revealing a discrete neuroimmune circuit substrate for mood comorbidity in chronic pain.