Pretraining vagus nerve stimulation differently influences cognition and anxiety-like behavior in male and female rats across estrous cycle stages

Vagus nerve stimulation (VNS) has previously been shown to enhance cognitive performance in rats when administered post-behavioral paradigm training. However, the effects of VNS administered pre-training, and its potential sex and hormonal dependencies, are not well understood. Here, we aimed to investigate the effects of a single pre-behavioral paradigm training session of VNS on cognitive performance and anxiety-like behaviors in male and female rats. The study also explored the influence of the estrous cycle on these outcomes in female rats. Male and female Sprague-Dawley rats underwent surgical implantation of electrode cuff around the left cervical branch of the vagus nerve (VN) and VNS was administered 30 min before the behavior paradigm. Performance on the elevated zero maze (EZM) was assessed immediately after VNS, whereas passive avoidance task (PAT), and novel object recognition (NOR) performance were assessed 24 h after training. In males, pre-training VNS had no significant effects on anxiety, aversion learning, or memory recognition. VNS acted as an anxiolytic in females. Estrous cycle-dependent detriments in aversion learning were also exhibited in stimulated female rats. There was no change in recognition memory in female rats after VNS. This study highlights the importance of stimulation timing, sex, and hormonal status as key variables in optimizing VNS protocols.