The primary somatosensory cortex mediates trigeminal neuralgia induced depressive-like behaviors through an indirect pathway targeting the lateral habenula

Abstract Background Trigeminal neuralgia frequently co-occurs with depression, aggravating clinical outcomes. The primary somatosensory cortex (S1), a key pain-processing region, exhibits hyperactivity linked to chronic pain. Moreover, S1 integrates nociceptive inputs to modulate pain-related affective disturbances. However, it remains unclear whether S1 contributes to trigeminal neuralgia-induced depressive-like behaviors and the underlying circuit mechanisms. Methods A mouse model of trigeminal neuralgia was established via chronic constriction injury of the infraorbital nerve (CION). Mechanical pain threshold and depressive-like behaviors were evaluated using von Frey, open field, tail suspension, forced swim, and sucrose preference tests. Neuronal activity was monitored by immunofluorescence, electrophysiology, and fiber photometry. Viral tracing identified projections from glutamatergic neurons in the primary somatosensory barrel cortex (S1BF) to the lateral habenula (LHb). Chemogenetic approaches were employed to bidirectionally modulate S1BF and LHb glutamatergic neurons and their connecting circuit. Results In mice with trigeminal neuralgia, glutamatergic neurons in both S1BF and LHb showed increased activation. Chemogenetic inhibition of these neurons in either region alleviated hyperalgesia and depressive-like behaviors in CION mice. Viral tracing revealed an excitatory three-node disynaptic S1BF-ACC-LHb circuit. Selective inhibition of this pathway reversed hyperalgesia and depressive-like behaviors in CION mice, whereas its activation lowered mechanical pain threshold and induced depressive-like behaviors in naive mice. Conclusion This study reveals a circuit mechanism by which the S1BF indirectly projects to the LHb via the anterior cingulate cortex (ACC), thereby mediating trigeminal neuralgia-induced depressive-like behaviors. Overactivation of the S1BF-ACC-LHb excitatory three-node disynaptic circuit underlies hyperalgesia and depressive-like behaviors in CION mice.