Brain grey matter volume reduction and anxiety-like behavior in lipopolysaccharide-induced chronic pulmonary inflammation rats: A structural MRI study with histological validation

Abstract

While there have been multiple fMRI studies into the brain functional changes after acutely stimulated peripheral infection, knowledge for the effect of chronic peripheral infection on whole brain morphology is still quite limited. The present study was designed to investigate the brain structural and emotional changes after peripheral local infection initiated chronic systemic inflammation and the relationship between circulating inflammatory markers and brain grey matter. Specifically, in-vivo T2-weighted MRI was performed on rats with lipopolysaccharide (LPS)-induced chronic pulmonary inflammation (CPI) and those without. Grey matter volume was quantified using diffeomorphic anatomical registration through exponentiated lie (DARTEL) enhanced voxel-based morphometry followed by between-group comparison. Open field experiment was conducted to test the potential anxiety-like behaviors after CPI, along with the ELISA estimated inflammatory markers were correlated to grey matter volume. Guided by image findings, we undertook a focused histological investigation with immunefluorescence and Nissl staining. A widespread decrease of grey matter volume in CPI-model rats was revealed. 8 of the 12 measured inflammatory markers presented differential neuroanatomical correlation patterns with three of the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and CRP being the most notable. Lower grey matter volumes in some of the inflammatory markers related regions (amygdala, CA2 and cingulate cortex) were associated with more-severe anxiety-like behaviors. Furthermore, grey matter volumes in amygdala and CA3 were correlated negatively with the expressions of glial proteins (S100β and Nogo-A), while the grey matter volume in hypo-thalamus was changing positively with neural cell area. Overall, the neuroanatomical association patterns and the histopathology underpinning the MRI observations we demonstrated here would probably serve as one explanation for the cerebral and emotional deficits presented in the patients with CPI, which would furthermore yield new insights into the adverse effects the many other systemic inflammation and inflammatory autoimmune diseases would pose on brain morphology.