Vagus nerve modulation of hippocampus function. - Project Summary / Abstract The vagus nerve is the main conduit of information between the gastrointestinal (GI) tract and the central nervous system. In addition to communicating meal-related satiation signals from the GI tract to the brain to control meal size1, vagal afferent neurons (VAN) also relay information from the gut to the brain to promote the function of the hippocampus (HPC) – an integral brain structure in the regulation of learning and memory. Emerging evidence indicates that the vagus nerve plays a role in the regulation of cognitive processes such as motivation, anxiety, and memory2. Work from our group has revealed that selective ablation of GI- originating vagal afferents impairs HPC-dependent memory function in rodents3,4. The neurobiological mechanisms by which VAN promote memory function, however, remain unclear. Recently, the primary mentor’s group identified the medial septum (MS) as a region relaying signals between the VAN and the dorsal subregion of the HPC (HPCd)3. The MS extensively innervates the HPCd with acetylcholine (ACh)-producing fibers and is integral in the regulation of HPC-dependent memory function5. Thus, we hypothesize that physiological signals that originate from the gut that engage the VAN to modulate HPCd function via MS ACh signaling. Further, reductions in MS-to-HPCd ACh signaling are considered a pathological hallmark of Alzheimer’s disease (AD)6. AD currently affects ~24 million individuals and is marked by reduced ACh tone in the HPCd6. We hypothesize that potentiation of the VAN-HPCd cholinergic pathway through vagus nerve stimulation (VNS) may yield neuroprotective effects against AD and related dementias. Given the uncovered role of the vagus nerve in the regulation of learning and memory, understanding the neural substrates for how the vagus nerve regulates memory in the HPCd is critical for the development of novel therapeutics to treat and/or prevent AD. Preliminary results from fiber photometry recordings indicate that HPCd ACh is released during food consumption, with robust elevations in HPCd ACh release levels upon satiation. Aim 1 experiments build off these findings by examining HPCd ACh responses during intragastric infusion of different macronutrients, peripheral delivery of known satiation signals, and during the intake of isolated macronutrients to unravel what drives meal-induced HPCd ACh release. Moreover, given that various VAN loss-of-function models (e.g., sub-diaphragmic vagotomy), which have been established to cause HPC dysfunction, yield dysregulation of HPCd ACh signaling, we posit that vagus nerve signaling promotes HPC function. Given that VNS paired to ingestive events is sufficient to rescue diet-induced HPC memory deficits, Aim 2 experiments will use a transgenic rodent model of AD (TgF344-AD)7,8 to assess meal-associated HPCd ACh responses using fiber photometry and explore the therapeutic potential of our novel VNS approach for improving AD-associated cognitive impairments. Overall, the outcomes of the proposed research will improve our understanding of the role of VAN in physiological HPC memory maintenance and AD etiology.
