By Christopher Anderson, Alexis Miller

Faculty Mentor: Dr. Parrish Waters

Abstract

Semaglutide (marketed as Ozempic, Wegovy, et al.) is an agonist of the glucagon-like peptide-1 receptor (GLP-1-R) that enjoys a high use rate for both its on-label (therapy for diabetes mellitus) and off-label (appetite quenching) effects. Semaglutide also has positive effects on cognitive performance, although the mechanisms and details of these effects are not established. To explore the mechanisms that mediate the pro-cognitive effects of Semaglutide, we compared the effects of this drug to an environmental enrichment (EE) paradigm; a wealth of literature has established reliable and potent cognitive enhancing effects of EE. We designed a 3×2 experimental framework, administering Semaglutide, Exendin (a GLP-1-R antagonist), or vehicle (.9% Saline) to mice housed in EE or standard social cages. We used female CD-1 mice to minimize fighting and promote genetic diversity. In addition to measuring body mass and wheel running activity, we assess levels of plasma glucocorticoids and glucocorticoid receptors in the hippocampus. The hippocampal glucocorticoid system is closely linked to cognitive performance. Hippocampal glucocorticoid activity can influence the expression of brain derived neurotrophic factor and glutamatergic NMDA receptors, both of which also promote cognitive performance. This
physiological study aims to elucidate the potential pro-cognitive effects of Semaglutide.