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Defining the Role of the 5-HT4 Receptor in the Brain, Behavior, and Gut Abnormalities Resulting from In Utero SSRI Exposure

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[Technical Report, Annual Report]

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Depression during pregnancy is common. Because untreated maternal depression during pregnancy is associated with negative psychiatric and gastrointestinal GI developmental outcomes in children, treatment is paramount. The safest and first-line therapy, selective serotonin reuptake inhibitors SSRIs, however, also cause GI and psychiatric issues. Our laboratories have validated the first mouse model of perinatal SSRI exposure that demonstrates an impact of perinatal SSRI exposure on all four parts of the brain-gut-behavior-microbiome BGBMaxis. Utilizing this model, we generated key evidence confirming that developmental SSRI fluoxetine exposure leads to long-lasting alterations in brain wiring, behavior depression, anxiety, enteric nervous system ENS development, GI functions constipation, altered intestinal epithelial growth and the intestinal microbiome. Importantly, the BGBM abnormalities demonstrated in our model mimic those demonstrated in children exposed to SSRIs perinatally, making a translational in-depth analysis of the SSRI-BGBM axis interplay now feasible. Further, we have utilized this model to demonstrate that treatment with a serotonin 4 receptor 5-HT4R antagonist, piboserod, during early development, rescues intestinal, behavioral and enteric microbiota phenotypes in mice exposed to SSRIs during the perinatal period. In this proposal we aim to 1 elucidate brain,gut and microbiome-based mechanisms that underlie the abnormalities associated with perinatal SSRI exposure, 2 extend our preclinical studies of piboserod to define its developmental effects and therapeutic window and 3 utilize novel transgenic mouse models that selectively eliminate the serotonin reuptake transporter SERT, the critical protein antagonized by SSRIs, in the brain and t he intestine, to delineate the distinct roles of brain and gut serotonin SERT in the BGBM axis.


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  • Medicine and Medical Research

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[A, Approved For Public Release]