Role of left and right vagus nerves in linking peripheral adrenergic signals to contextual fear memory

Stress-induced physiological changes are crucial for adaptive responses to threats. Catecholamines, specifically epinephrine, activate peripheral β-adrenergic receptors, facilitating contextual fear memory consolidation. The vagus nerve is thought to be essential in transmitting physiological signals to the brain, influencing emotional memory consolidation. We aimed to evaluate the vagus nerve's role in contextual fear memory strengthening induced by epinephrine. Male 129 × 1/SvJ mice underwent bilateral subdiaphragmatic vagotomy, right or left cervical vagotomy, or sham surgeries. After a seven-day recovery, mice were subjected to the fear conditioning paradigm, receiving three foot shocks on conditioning day, followed by contextual reminder exposure. Epinephrine (0.1 mg/kg, intraperitoneal, i.p.) was administered to a subset of left cervically vagotomized mice 3 min before each session. Freezing behavior was evaluated. Catecholamines were quantified by reverse-phase high-performance liquid chromatography (HPLC) with electrochemical detection. Subdiaphragmatic vagotomy did not alter freezing behavior on both days. In cervical vagotomies, while no differences were observed on the conditioning day, a significant decrease in freezing behavior was observed on the context day. In left cervically vagotomized mice, epinephrine administration significantly increased freezing behavior. In conclusion, unilateral left or right cervical vagotomy impaired contextual fear memory, contrary to subdiaphragmatic vagotomy. Impaired contextual fear memory in left cervical vagotomy was reversed by exogenous epinephrine, possibly due to the intact right cervical vagus. We suggest that stress-induced catecholamine release may activate thoracic peripheral β-adrenergic receptors and elevate systolic blood pressure, signals that are transmitted through the vagus nerve, influencing the hippocampus and facilitating contextual fear memory consolidation.