A glutamatergic ventrolateral periaqueductal gray-lateral habenula pathway is associated with depression-like behavioral measures in young adult male mice with trigeminal neuropathic pain.

内容摘要

Depression is a clinically important comorbidity of trigeminal pain disorders, including trigeminal neuralgia, yet the neural circuits linking persistent trigeminal nerve injury to negative affect remain incompletely understood. The present study aimed to investigate the involvement of the ventrolateral periaqueductal gray (vlPAG)-lateral habenula (LHb) pathway in depression-like behavioral measures in a young adult male mouse model of trigeminal neuropathic pain. A mouse model of trigeminal neuropathic pain was established in young adult male mice using infraorbital nerve chronic constriction injury (IoN-CCI). Spontaneous facial pain-related behavior and depression-like behavioral measures were assessed using facial grooming analysis, the sucrose preference test, the open field test, and the tail suspension test. c-Fos mapping, cell-type analysis, viral tracing, and chemogenetic manipulation of vlPAG glutamatergic neurons and the vlPAG-LHb pathway were performed to examine neuronal recruitment, anatomical connectivity, and behavioral relevance. In young adult male mice, IoN-CCI induced persistent facial grooming behavior as an index of spontaneous facial pain-related behavior and, by 4 weeks after surgery, was associated with depression-like behavioral changes without detectable alterations in body weight, general locomotor activity, or hindpaw mechanical and thermal sensitivity. c-Fos mapping and cell-type analyses showed a progressive increase in c-Fos expression in vlPAG neurons following IoN-CCI, with most labeled neurons identified as glutamatergic, suggesting recruitment of vlPAG glutamatergic neurons in this model. Chemogenetic inhibition of vlPAG glutamatergic neurons decreased depression-like behavioral measures, whereas chemogenetic activation increased these measures, without significantly altering facial grooming behavior used as an index of spontaneous facial pain-related behavior. Viral tracing provided anatomical evidence for a projection from the vlPAG to the LHb, and c-Fos expression in LHb neurons increased following IoN-CCI. Chemogenetic inhibition of the vlPAG-LHb pathway decreased depression-like behavioral measures, whereas chemogenetic activation increased these measures in IoN-CCI mice and was associated with similar behavioral changes in naive mice. These findings suggest that the vlPAG-LHb pathway is functionally associated with behavioral measures related to negative affect in a young adult male mouse model of trigeminal neuropathic pain, providing a circuit-level framework for understanding pain-associated affective disturbances. Not applicable.