Oxytocin remodels the brain-heart axis: intranasal treatment rescues PTSD-related deficits in persistent fear memory retention and cardiac autonomic dysfunction

Post-traumatic stress disorder (PTSD) is increasingly recognized as a brain-body disorder in which excessive retention of pathological fear memory coincides with profound cardiac autonomic dysregulation, substantially elevating cardiovascular morbidity, including the risk of myocardial infarction. Despite this dual burden, therapeutic strategies capable of concurrently rescuing the core persistent fear memory retention deficits and normalizing stress-induced cardiac autonomic dysfunction remain critically lacking. Here, using a single prolonged stress-induced rat model of PTSD, we found that intranasal oxytocin (OXT) administration not only alleviates pathological over-retention of fear memory but also rescues fear cue-elicited abnormalities in heart rate and heart rate variability. Crucially, cervical vagotomy abolished these cardioprotective effects, indicating that OXT’s cardiac regulatory actions rely on an intact vagus nerve pathway to re-establish cardiac autonomic homeostasis. Furthermore, in vivo electrophysiological recordings revealed that intranasal OXT robustly activates ventral tegmental area (VTA) dopamine (DA) neurons, elevating both the firing and burst rates. Immunofluorescence staining further confirms abundant OXT receptor expression within these DA neurons. Collectively, these results uncover a coordinated central-peripheral regulatory cascade modulated by intranasal OXT that mitigates PTSD-associated behavioral and physiological deficits, with VTA dopaminergic signaling likely serving as a major upstream mediator.