Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Author: Suarez AN1, Hsu TM2,3, Liu CM1,2, Noble EE1, Cortella AM1, Nakamoto EM2, Hahn JD4, de Lartigue G5,6, Kanoski SE7,8,9 Affiliation: <sup>1</sup>Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA. <sup>2</sup>Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA. <sup>3</sup>Department of Psychology, University of Illinois at Chicago, Chicago, Illinois, USA. <sup>4</sup>Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA. <sup>5</sup>The John B. Pierce Laboratory, New Haven, Connecticut, USA. gdelartigue@jbpierce.org. <sup>6</sup>Department of Cellular and Molecular Physiology, Yale Medical School, New Haven, Connecticut, USA. gdelartigue@jbpierce.org. <sup>7</sup>Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA. kanoski@usc.edu. <sup>8</sup>Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA. kanoski@usc.edu. <sup>9</sup>Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA. kanoski@usc.edu. Conference/Journal: Nat Commun. Date published: 2018 Jun 5 Other: Volume ID: 9 , Issue ID: 1 , Pages: 2181 , Special Notes: doi: 10.1038/s41467-018-04639-1. , Word Count: 159 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. PMID: 29872139 DOI: 10.1038/s41467-018-04639-1