Absence of Microglial Activation and Maintained Hippocampal Neurogenesis in a Transgenic Mouse Model of Crohn’s Disease

• Published in: Cells (Basel, Switzerland) Vol. 14; no. 11; p. 841
• Main Authors: Masanetz, Rebecca Katharina, Mundlos, Hanna, Stolzer, Iris, Winkler, Jürgen, Günther, Claudia, Süß, Patrick
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.06.2025; MDPI
• Subjects: adult hippocampal neurogenesis; Analysis; Animal cognition; Animals; Anxiety; Apoptosis; Brain; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-8; Cell Proliferation; Cognitive ability; Colon; Comorbidity; Crohn Disease - genetics; Crohn Disease - pathology; Crohn's disease; Dentate gyrus; Dentate Gyrus - pathology; Digestive system; Disease Models, Animal; Epithelial cells; Forebrain; Gastrointestinal tract; Genetic engineering; gut–immune–brain axis; Hippocampus; Hippocampus - pathology; Homeostasis; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbiota; Microglia; Microglia - metabolism; Microglia - pathology; Neurogenesis; Polyclonal antibodies; Progenitor cells; Small intestine; Transgenic mice; Massachusetts; Germany; United States > US; Japan; dentate gyrus; adult hippocampal neurogenesis; microglia; gut–immune–brain axis; inflammatory bowel disease
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells14110841

Adult neurogenesis in the hippocampal dentate gyrus (DG) is not only essential for learning and pattern separation, but it is also involved in emotional regulation. This process is vulnerable to local and peripheral inflammation, which is partly mediated by microglia in the DG. As Crohn’s disease (CD) is associated with neuropsychiatric comorbidity, including depression and cognitive impairment, a reduction in adult hippocampal neurogenesis by chronic gut-derived inflammation has been hypothesized. Here, we present the first study that examined the influence of chronic ileocolitis on microglia in the DG and on adult hippocampal neurogenesis in a transgenic mouse model of CD, which is generated by a constitutive knockout of caspase 8 in intestinal epithelial cells (IECs, Casp8ΔIEC mice). Structural and transcriptional analyses revealed that microglial cell proliferation and density in the DG as well as the expression of genes associated with their homeostasis and activation in the forebrain were maintained in 14- and 24-week-old Casp8ΔIEC mice compared to Casp8fl controls. Furthermore, different stages of adult hippocampal neurogenesis, including progenitor cell proliferation, maturation, and apoptosis of newly generated cells, were predominantly unaffected by chronic ileocolitis, except a potential minor phenotypic shift in maturating cells in 24-week-old mice. Together, we demonstrate largely preserved adult hippocampal neurogenesis, lacking signs of local inflammatory microglial activation despite chronic inflammation of the gut.