Trigeminal nerve stimulation modulates dopaminergic circuits and neuroinflammation to alleviate depression.

Abstract

BACKGROUND: Trigeminal nerve stimulation (TNS) is a promising noninvasive neuromodulation therapy for depression; however, its mechanisms remain unclear. OBJECTIVE: This study investigated antidepressant-like effects of TNS and its underlying mechanisms in post-traumatic brain injury depression (PTD). METHODS: The antidepressant efficacy of TNS was evaluated in multiple depression models using standardized behavioral assays. Peripheral mechanisms were probed by chemogenetic activation or inhibition of trigeminal ganglion (TG) neuronal subpopulations in Cre-line mice. Centrally, pathway-selective chemogenetic manipulations tested the role of the paraventricular nucleus-ventral tegmental area-nucleus accumbens (PVN-VTA-NAc) circuit, coupled with in vivo (GPCR)-activation-based dopamine (GRAB-DA) fluorescence monitoring to quantify dopamine dynamics. Receptor-specific contributions were assessed using shRNA knockdown of D1/D2 or D3 receptors (D1/D2 or D3) in the NAc. Cerebrospinal fluid (CSF) cytokine profiling was used to evaluate inflammatory modulation. Primary endpoints were analyzed after the 10-day TNS treatment and following a 10-day post-stimulation period. RESULTS: TNS alleviated depressive-like behaviors across models. TG TRPV1neurons are both necessary and sufficient for efficacy. Chemogenetic modulation of the PVN-VTA-NAc pathway reproduced or abolished TNS effects, while GRAB-DA recordings confirmed increased dopamine release during stimulation. In the NAc, D1/D2 knockdown impaired effects of treatment, whereas D3 knockdown eliminated persistence after stimulation. TNS reduced CSF cytokines in controls and D1/D2 knockdown mice, but not in D3 knockdown mice, indicating that early D3-dependent anti-inflammatory effects sustain long-term benefits. CONCLUSIONS: TNS alleviates depressive-like behaviors through TG TRPV1neurons and PVN-VTA-NAc circuit activation, with D1/D2 receptors mediating acute effects and D3 receptors maintaining lasting anti-inflammatory benefits.