Oxytocin ameliorates early life stress-induced anxiety-like behavior by normalizing corticotropin-releasing hormone neuron activity in the PVN.

Maternal separation (MS), a prevalent form of early life stress (ELS) exposure, elevates vulnerability to anxiety disorders in later developmental stages. Despite its clinical relevance, the neural mechanisms remain poorly defined. In this study, we demonstrate that ELS-exposed offspring exhibit sustained anxiety-like behaviors. Through integrated c-Fos immunostaining and whole-cell patch-clamp recordings, we identified hyperactivation of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVNCRH) of ELS mice, characterized by enhanced neuronal activity and increased intrinsic excitability. Critically, chemogenetic suppression of PVNCRH neurons effectively alleviated anxiety-like phenotypes in ELS mice. Systemic oxytocin (OXT) administration reversed ELS-associated anxiety behaviors and normalized both synaptic hyperexcitability and intrinsic hyperactivation of PVNCRH neurons. Importantly, chemogenetic activation of PVNCRH neurons abolished OXT's anxiolytic effects. These findings delineate a neurobiological pathway through which ELS programs anxiety susceptibility, and identify OXT-mediated regulation of PVNCRH neuronal excitability as a potential therapeutic strategy for stress-related psychopathologies.