The Dopaminergic Spinal Trigeminal Nucleus Caudalis-Hippocampus Pathway Modulates TMD-Associated Depression via the DRD2/NF-κB/LEPR Signaling Axis

Temporomandibular disorders (TMD), prevalent orofacial conditions with complex etiologies, are frequently accompanied by emotional disturbances whose central nervous mechanisms remain poorly understood. Here, using a unilateral anterior crossbite (UAC) mouse model combined with hippocampal neuronal cultures, we investigated the neural substrates underlying TMD-associated depression. Behavioral analyses revealed that UAC mice exhibited significant depressive-like behaviors. Viral tracing and chemogenetic approaches identified a novel dopaminergic pathway from the spinal trigeminal nucleus caudalis (SpVc) to the hippocampus (HPC). Functional manipulation of this circuit demonstrated that chemogenetic inhibition of SpVc dopaminergic neurons (hM4Di activation) induced depressive-like behaviors, while post-TMD activation (hM3Dq) reversed these behavioral deficits. Additionally, UAC mice exhibited reduced hippocampal expression of dopamine receptor D2 (DRD2) and leptin receptor (LEPR). In vitro experiments established that DRD2 overexpression upregulated LEPR through nuclear factor kappa-B (NF-κB) phosphorylation, while DRD2 inhibition downregulated LEPR, defining a functional DRD2-NF-κB-LEPR signaling axis. Critically, adeno-associated virus (AAV)-mediated DRD2/LEPR overexpression in the hippocampus ameliorated depressive-like behaviors in UAC mice. These findings collectively reveal a previously unrecognized SpVc-HPC dopaminergic circuit that modulates TMD-related depression through the DRD2-NF-κB-LEPR axis, offering new insights into potential therapeutic strategies for TMD-associated neuropsychiatric comorbidities.