Gut vagal sensory signaling regulates hippocampus function through multi-order pathways

Andrea N Suarez,Emily M Nakamoto,Ted M Hsu,Alyssa M Cortella,Joel D Hahn,Guillaume De Lartigue,Scott E Kanoski,Clarissa M Liu,Emily E Noble

doi:10.1038/s41467-018-04639-1

Abstract

The vagus nerve is the primary means of neural communication between the gastrointestinal (GI) tract and the brain. Vagally mediated GI signals activate the hippocampus (HPC), a brain region classically linked with memory function. However, the endogenous relevance of GI-derived vagal HPC communication is unknown. Here we utilize a saporin (SAP)-based lesioning procedure to reveal that selective GI vagal sensory/afferent ablation in rats impairs HPC-dependent episodic and spatial memory, effects associated with reduced HPC neurotrophic and neurogenesis markers. To determine the neural pathways connecting the gut to the HPC, we utilize monosynaptic and multisynaptic virus-based tracing methods to identify the medial septum as a relay connecting the medial nucleus tractus solitarius (where GI vagal afferents synapse) to dorsal HPC glutamatergic neurons. We conclude that endogenous GI-derived vagal sensory signaling promotes HPC-dependent memory function via a multi-order brainstem–septal pathway, thereby identifying a previously unknown role for the gut–brain axis in memory control.

Highlights

The vagus nerve is the primary means of neural communication between the gastrointestinal (GI) tract and the brain
The present study investigated the endogenous role of GIderived vagus nerve signaling on a variety of HPC-dependent memory processes that involve the following: (1) processing of external visuospatial stimuli15; (2) discrimination learning based on interoceptive energy status cues6; and (3) social transmission of olfactory-related food cues16
Repeated-measures analysis of variance (ANOVA) analyses across days revealed a significant day × group interaction (F[1,13] = 5.564, p = 0.0347), with Newman–Keuls’ post hoc analyses confirming a significant sham vs. subdiaphragmatic vagotomy (SDV) group difference on day 3 (p = 0.0047) but not on day 1

Summary

Introduction

The vagus nerve is the primary means of neural communication between the gastrointestinal (GI) tract and the brain. Consistent with a role for vagal signaling in memory function, vagus nerve stimulation enhances memory , facilitates HPC neurogenesis, and increases HPC expression of brain-derived neurotrophic factor (BDNF) , a neurotrophin that promotes neuronal survival and differentiation, as well as synaptic plasticity. To dissociate between the role of GI vagal sensory vs motor signaling on HPC-dependent memory, we utilized total subdiaphragmatic vagotomy (SDV; eliminates all GI vagal afferents and efferents) and a novel rodent surgical approach for selective GI vagal deafferentation in which a SAP conjugated to cholecystokinin (CCK-SAP) is injected into the nodose ganglia (overview of approaches, b) This recently established procedure eliminates ~ 80% of GI-derived vagal sensory input to the brain while leaving intact all brain-to-gut vagal motor signaling, and supradiaphragmatic and colonic vagal sensory signaling. Using monosynaptic and multisynaptic virus-based neural pathway tracing methods, we identified a multi-order pathway connecting the medullary mNTS to the dorsal HPC via medial septum (MS) input to HPC glutamatergic neurons

Methods

Results

Conclusion