Project Summary/Abstract: The gut-brain axis, the bidirectional communication between the central nervous system (CNS) and enteric nervous system, has become implicated in numerous pathologies in the CNS, many of which result in cognitive impairments. Neuroinflammation has been identified as a critical mechanistic mediator of cognitive decline and the gut-brain axis is emerging as an important regulator of peripheral and central inflammation. A chief component of this immunomodulatory axis is the vagus nerve, as it mediates the cholinergic anti-inflammatory network (CAIN) in both the CNS and periphery. Gastrointestinal (GI) vagal afferents extending from the GI tract to the brain have been shown to activate the hippocampus, an essential integration center for learning and memory. Accordingly, the goal of this study is to investigate the vagal gut-brain circuit regulating hippocampal neurochemistry, neuroinflammation and cognition which remains poorly understood. This proposal utilizes a highly innovative technique developed by my collaborator Dr. Guillaume de Lartigue that selectively ablates ~80% of GI vagal afferents with a saporin (SAP) toxin tagged with the GI hormone cholecystokinin (CCK). I will then assess how impairing GI vagal afferents affects cholinergic neurochemistry and neuroinflammation in the hippocampus with in vivo microdialysis, HPLC and biochemical assays. I will also assess the behavioral consequences of GI vagal ablation with the novel object recognition task as Dr. de Lartigue has shown this technique impairs hippocampal-dependent memory processes. To further elucidate this mechanism, I will then assess if these hippocampal impairments can be rescued by a positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) as these receptors on the surface of macrophages, microglia and astrocytes mediate the CAIN. Thus, the overarching hypothesis of this proposal is that positive allosteric modulation of α7 nAChRs rescues hippocampal cholinergic deficits induced by the ablation of gastrointestinal vagal afferents. Completion of these studies will provide insight into the immunoregulatory actions of the gut-brain axis and the integral role this relationship plays in various CNS disorders, especially those with neuroinflammation and cognitive impairments. In addition, this project provides me ample opportunities to diversify my technical skills with a team of mentors who are experts in their fields and have a strong history of collaboration and federal funding. This strong mentorship team also provides extensive networking and dissemination opportunities that will shape me into a productive, independent researcher.