Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: FROM THE GUT TO THE BRAIN: EFFECTS OF BOWEL INFLAMMATION ON SYNAPTIC TRANSMISSION AND GLIAL PROPERTIES

Inflammatory bowel diseases (IBD) affect the gastrointestinal tract and can lead to extra-intestinal manifestations associated with cerebral function, including depression and anxiety. Previous studies have shown that during acute inflammation, different brain areas, including hippocampus, undergo alterations in glial properties and glutamatergic synaptic transmission, along with impairment of blood-brain barrier (BBB) permeability, leading to immune cell infiltration and increase of cytokines levels. However, a comprehensive understanding of the mechanisms involved remains elusive. This study aims to elucidate the cellular and molecular mechanisms underlying the alterations in the central nervous system. Using a murine model of acute peripheral inflammation induced by 2,4-Dinitrobenzenesulfonic acid hydrate (DNBS), we explored the impact of the gut-brain axis on cerebral function and identified potential mediators of central dysfunction. Through transcriptomic and immunofluorescence analyses, we show that colitis induces neuroinflammation and glial reactivity. In addition, by means of electrophysiological recordings, we assessed the effects of bowel inflammation on excitatory and inhibitory synaptic transmission in the hippocampus. Finally, we investigated the molecular mechanisms underlying the hippocampal alterations induced by colitis through metabolomic analysis. Our findings reveal significant changes in the hippocampal transcriptome, glial reactivity, and synaptic transmission, as well as changes in gut and hippocampal metabolites in the DNBS model. In conclusion, our study demonstrates that bowel inflammation and dysbiosis are associated with hippocampal dysfunctions, providing new perspectives for future investigations.