Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis

• Published in: Brain, behavior, and immunity behavior, and immunity, 2018-02, Vol.68, p.261-273
• Main Authors: Dunphy-Doherty, Fionn, O'Mahony, Siobhain M., Peterson, Veronica L., O'Sullivan, Orla, Crispie, Fiona, Cotter, Paul D., Wigmore, Peter, King, Madeleine V., Cryan, John F., Fone, Kevin C.F.
• Format: Article
• Language: English
• Subjects: Animals; Anxiety; Behavior, Animal - drug effects; Brain - metabolism; Cytokines; Dentate Gyrus - physiopathology; Disease Models, Animal; Gastrointestinal Microbiome - physiology; Hippocampus - physiopathology; Immunity - physiology; Interleukin-10; Interleukin-6; Isolation rearing; Learning; Learning and memory; Male; Memory; Microbiota; Motor Activity - drug effects; Neurogenesis; Rats; Schizophrenia; Schizophrenia - physiopathology; Social Behavior; Social Isolation; Weaning
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.10.024

•Rat social isolation (SI) at weaning alters behavior and neurochemistry resembling schizophrenia.•The role of changed gut microbiota in development of the SI syndrome is examined herein.•SI increased activity, reduced associative learning, neurogenesis and hippocampal IL-6 and IL-10.•Correlations existed between microbiota, IL-6 and IL-10, conditioned freezing and exploration.•SI alters microbiota, cytokine and hippocampal function akin to schizophrenia pathophysiology. Early-life stress is an established risk for the development of psychiatric disorders. Post-weaning isolation rearing of rats produces lasting developmental changes in behavior and brain function that may have translational pathophysiological relevance to alterations seen in schizophrenia, but the underlying mechanisms are unclear. Accumulating evidence supports the premise that gut microbiota influence brain development and function by affecting inflammatory mediators, the hypothalamic–pituitaryadrenal axis and neurotransmission, but there is little knowledge of whether the microbiota-gut-brain axis might contribute to the development of schizophrenia-related behaviors. To this end the effects of social isolation (SI; a well-validated animal model for schizophrenia)-induced changes in rat behavior were correlated with alterations in gut microbiota, hippocampal neurogenesis and brain cytokine levels. Twenty-four male Lister hooded rats were housed in social groups (group-housed, GH, 3 littermates per cage) or alone (SI) from weaning (post-natal day 24) for four weeks before recording open field exploration, locomotor activity/novel object discrimination (NOD), elevated plus maze, conditioned freezing response (CFR) and restraint stress at one week intervals. Post-mortem caecal microbiota composition, cortical and hippocampal cytokines and neurogenesis were correlated to indices of behavioral changes. SI rats were hyperactive in the open field and locomotor activity chambers traveling further than GH controls in the less aversive peripheral zone. While SI rats showed few alterations in plus maze or NOD they froze for significantly less time than GH following conditioning in the CFR paradigm, consistent with impaired associative learning and memory. SI rats had significantly fewer BrdU/NeuN positive cells in the dentate gyrus than GH controls. SI rats had altered microbiota composition with increases in Actinobacteria and decreases in the class Clostridia compared to GH controls. Differences