Early life Western Diet exposure impairs vagus nerve-mediated hippocampus cholinergic signaling

Chronic exposure to a Western diet (WD) elicits hippocampal (HPC)-dependent memory impairment. One potential unexplored mechanism for these effects involves impaired vagus afferent nerve (VAN) signaling, as VAN signaling promotes HPC function, and WD consumption blunts the capacity of vagally-mediated gut signals to communicate to the brain. The medial septum (MS) is an anatomical relay between the brainstem and the HPC, and the MS extensively innervates the HPC with acetylcholine (ACh)-releasing fibers. Thus, we hypothesized that VAN signaling engages the HPC via MS ACh release, and further, that impairments in this signaling pathway underlie WD-associated HPC dysfunction. Using in vivo fiber photometry and fluorescent ACh sensors (iAChSnFR) in adult (Postnatal day 56-75) male Sprague Dawley rats, we demonstrate that HPC ACh binding is elevated immediately following consumption of a meal (n=10). Additional results revealed that these meal-induced elevations in HPC ACh binding were eliminated in animals who underwent a surgical subdiaphragmatic vagotomy (SDV), thus identifying a role for vagal signaling in mediating postprandial HPC ACh signaling (n=5-6/group). To explore how a WD affects this outcome, we recorded HPC ACh release in animals chronically exposed to a WD during development (Post-natal days 26-56) while consuming a meal during adulthood. Results reveal that, similar to SDV rats, meal-induced elevations in HPC ACh binding were eliminated in the WD group (n=6-8/group). Further, Western blot analyses revealed comparable reductions in HPC protein expression of vesicular ACh transporter, an indicator of ACh HPC tone, in SDV and WD rats relative to controls. Collectively, our findings identify ACh signaling as a neural substrate for gut-originating VAN potentiation of HPC function, and that impairments in this signaling pathway may underlie WD-induced HPC dysfunction. NIH funding: •DK104897 •DK123423 •DK118402 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.