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Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity \u2014 in response to gastric distention \u2014 was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a \u201cbottom-up\u201d pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.<\/jats:p>","DOI":"10.1172\/jci.insight.144046","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T09:01:30Z","timestamp":1614502890000},"source":"Crossref","is-referenced-by-count":48,"title":["Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6000-567X","authenticated-orcid":true,"given":"Zachary A.","family":"Cordner","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5181-6366","authenticated-orcid":true,"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liansheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9398-8796","authenticated-orcid":true,"given":"Kellie L.","family":"Tamashiro","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Bhargava","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology and The Center for Reproductive Sciences, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy H.","family":"Moran","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj Jay","family":"Pasricha","sequence":"additional","affiliation":[{"name":"Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(18)30003-7"},{"key":"B2","doi-asserted-by":"crossref","unstructured":"Drossman DA. 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