Vagal afferent nerve ghrelin signaling influences energy balance and episodic memory

Abstract

Vagal afferent nerve (VAN) signaling sends sensory information from the gut to the brain and participates in the regulation of meal size and blood glucose control. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including hippocampus(HPC)‐ dependent memory function. The nodose ganglia (VAN neurons) express receptors for various gut‐derived endocrine signals, however, the function of these receptors with regards to feeding behavior, glucose regulation, and HPC‐dependent memory is poorly understood. We hypothesized that these VAN‐mediated behavioral and physiological processes are influenced by ghrelin, a stomach‐derived orexigenic hormone, via communication to its receptor (growth hormone secretagogue receptor [GHSR]) expressed on gut‐innervating VAN terminals. To examine this hypothesis, adult male rats received bilateral nodose ganglion injections of an adeno‐associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a scrambled control AAV) for RNA interference‐mediated VAN GHSR knockdown. Meal‐pattern analyses revealed a significant increase in meal frequency in the VAN GHSR knockdown group compared with controls, coupled with a nonsignificant trend in reduced average meal size such that cumulative 24h food intake did not differ between groups. Results from an intraperitoneal glucose tolerance test revealed impaired glucose tolerance in VAN GHSR knockdown animals vs. controls. Despite no differences in cumulative 24h food intake, the VAN GHSR knockdown group also had significantly increased body weight gain compared with controls. Lastly, to examine the role of VAN GHSR signaling in HPC‐dependent memory function, the rats were tested in novel object in context task that measures contextual episodic memory. Results reveal that VAN GHSR knockdown impairs memory performance in this task, yet has no effect on measures of anxiety‐like behavior or levels of general activity. Collectively, these results reveal that VAN GHSR signaling is important for the control of both energy balance as well as HPCdependent memory function.