Sapienza starting grant research proposal 2019

Clinical and preclinical data suggest that metabolic dysregulation induced by a long‐term high‐fat diet (HFD) may elicit neurobehavioral alterations through the ascent of neuropathological signals by the “gut-brain axis”, favored by an intestinal barrier alteration referred as “leaky gut syndrome”. Our earlier discoveries show that enteric glial cells (EGCs) become activated in the HFD-induced leaky gut condition, leading to impaired neurogenesis in both the enteric nervous system (ENS) and central nervous system (CNS), and the development of anxiogenic and depressive symptoms. However, the underlying mechanisms by which activated EGCs may negatively affect emotionality are obscure. In this context, cholecystokinin (CCK), a gut-brain peptide found abundantly in the peripheral and central nervous systems, plays a key role in the peripheral and central regulation of appetite and food intake. Alterations in CCK levels may affect conditions such as obesity and metabolic disorders, as well as neuropsychiatric diseases. CCK levels are positively correlated with anxiety- and depressive-like behaviors in several models of metabolic diseases, suggesting CCK contributes to neuropathological effects on mood. The goal of this proposal is to explore CCK role in EGCs dysfunction occurring in HFD, linking leaky gut-induced enteric glia activation to mood disorders. To this end, the scientific aims of this proposal will test whether: (1) alterations in CCK peptide levels and/or its receptors occurs within the ENS in HFD-induced leaky gut, (2) CCK signal dysfunction is restricted to the intestinal level and how it is associated with neuropathological signaling to the CNS, (3) EGCs and enteric neurons produce/respond actively to CCK in a condition of gut hyperpermeability, and finally (4) linking these sequels of events to the observed neurogenesis markers impairment and to the onset of anxiogenic/ depressive-like symptoms in HFD-treated mice.