Gut-Derived Vagus Nerve Signaling Promotes Memory Function

Background: Gut-derived vagus nerve signaling is known to promote meal termination, yet emerging findings support an additional role in higher-order cognitive processes. Our group has identified a multi-synaptic pathway connecting gut-derived vagal afferents to the hippocampus, and further, that subdiaphragmatic vagal afferent ablation impairs hippocampal-dependent memory. Based on these findings we hypothesized that [1] loss of vagus nerve signaling increases the risk for dementia in humans, and [2] gut-derived vagus nerve stimulation improves hippocampal-dependent memory functions in a rat model of diet-induced cognitive impairment. Methods: [1] Using data from the Swedish National Patient Registry, hazard ratios (HR) of dementia diagnosis were compared between individuals who underwent a vagotomy (for peptic ulcer disease) versus age-matched healthy controls, with sex and age as confounding factors. [2] Male rats were implanted with a sham or functional subdiaphragmatic vagus nerve stimulation (VNS) device and were fed a high-fat-high-sucrose diet (HFHS) for 5 weeks prior to testing in the "novel object in context" (NOIC) and "meal place recognition" (MPR) memory tasks. Results: [1] Vagotomy increased the risk for dementia later in life relative to healthy controls (HR: 3.401) and this was driven by truncal (HR: 4.895) and not selective (HR: 2.543) vagotomy. [2] VNS rats displayed reduced meal size relative to sham rats, although no significant differences in body weight or caloric intake were observed. While HFHS sham rats demonstrated hippocampal dysfunction, evidenced as failure to learn either the NOIC or MPR tasks, VNS prevented the expression of these diet-induced memory deficits. Conclusions: These findings identify a potential role for gut-derived vagus nerve signaling in the etiology of human dementia. The efficacy of VNS in alleviating hippocampal-dependent memory function is supported by additional preclinical results. Collective findings highlight the potential for VNS in dementia treatment.