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

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/DRN^Glu), driving anxiety and depression.
• Microglia-specific Nlrp3 deletion or IL-1R1 blockade prevents pain-induced affective deficits.
• An excitatory vlPAG/DRN^Glu to BNST^GABA pathway mediates the affective component of neuropathic pain.

Conclusions:

• A novel neuroimmune circuit involving microglia, vlPAG/DRN^Glu neurons, and BNST^GABA neurons underlies the affective comorbidities of neuropathic pain.
• This microglia-vlPAG/DRN^Glu-BNST^GABA axis translates peripheral injury signals into maladaptive emotional states.
• Targeting this circuit offers potential therapeutic strategies for chronic pain and associated mood disorders.