Activation of the PVN-PVT oxytocinergic circuit mediates the anxiolytic effect of L-Cysteine in mice under chronic restraint stress.

Anxiety disorders are highly prevalent mental illnesses characterized by pathological worry and anxiety, often comorbid with depression and insomnia, which complicate treatment. This study aimed to investigate the anxiolytic potential and underlying neural mechanisms of L-Cysteine in a mouse model of chronic restraint stress (CRS). Using behavioral tests across multiple dose groups, administration of medium-dose L-Cysteine (50 mg/kg) alleviated anxiety-like behaviors induced by CRS. Immunofluorescence staining showed that L-Cysteine reversed CRS-induced neuronal hyperactivation in the paraventricular thalamic nucleus (PVT). High-throughput RNA sequencing indicated activation of the Oxytocin signaling in the PVT, which was validated by qRT-PCR and ELISA. Further tracing revealed that exogenous L-Cysteine accumulates in the paraventricular hypothalamic nucleus (PVN) and enhances Oxytocin synthesis in PVN-PVT projection neurons. Together, these findings demonstrate that L-Cysteine exerts its anxiolytic effects by activating the PVN-PVT oxytocinergic pathway, revealing a specific neurochemical mechanism and suggesting a potential therapeutic strategy for stress-related anxiety.