Maternal Separation Stress Augments Autistic-Like Behaviors Provoked Following Colitis Induced With Acetic Acid in Mice: Possible Role of Hippocampus Structural Alteration, Neuroinflammation, and mTOR.

Abstract

Inflammatory bowel disease (IBD) is an enduring inflammatory complaint with extraintestinal consequences, including autism spectrum disorder (ASD). This experiment was directed to test the influence of maternal separation (MS) stress on the comorbidity of ASD-like behaviors provoked following experimental colitis in male mice, emphasizing the relevance of hippocampal structure, mammalian target of the rapamycin (mTOR), and neuroinflammation. The 32 male Naval Medical Research Institute (NMRI) mice were randomly assigned into four groups, including the MS mice with or without induction of colitis and control mice with or without induction of colitis. Seven days after induction of colitis using acetic acid, mice subjected to the behaviors related to autism, including sociability and social preference indexes, passive avoidance memory, and repetitive and anxiety-like behaviors, were assessed. Then, the colon and hippocampus were dissected out. Diameter and percent of dark neurons of the CA1 and CA3 in the hippocampus plus histopathological change in the colon were assessed. RT-PCR measured TLR4, TNF-α, IL-1β, and mTOR mRNA expression in the hippocampus. Outcomes revealed that MS amplified the negative effects of colitis on related behaviors to autism. MS augmented effect of colitis on reduction of diameters and enhancement of dark neurons in the CA1 and CA3 parts along with histopathological changes of the colon. The hippocampal mRNA expression of TLR4, IL-1β, TNF-α, and mTOR more increased in the group that underwent both MS and colitis. These findings, partially, suggest that MS intensified the influence of colitis on ASD-like phenotype, reinforcing, in part, the role of hippocampal neuroinflammation, mTOR as well as structural hippocampal changes.