Early alterations of functional connectivity, regional brain volumes and astrocyte markers in the beta-sitosterol beta-d-glucoside (BSSG) rat model of parkinsonism

Abstract

The β-sitosterol-β-ᴅ-glucoside (BSSG) rat model of experimental parkinsonism develops pathological behaviour and motor changes that progress over time. The purpose of this study was to identify early changes in structure and function of the brain of rats treated with BSSG using both structural and resting-state functional MRI. BSSG and non-BSSG rats were fed five days a week for sixteen weeks, then underwent in vivo MRI scans and an assessment of motor performance 2 and 8 weeks later (18 and week 24 from BSSG). Groups of rats were killed at weeks 19 and 25, then imaged again with MR ex vivo, and immunostained for tyrosine hydroxylase (TH). Since BSSG may interfere with cholesterol metabolism in astrocytes, we also studied potential target engagement and measured levels of astrocyte markers GFAP and S100b. At both studied timepoints, functional connectivity (FC) between brain areas with intermediate connectivity was decreased, but brain volumes increased in the BSSG-treated rats. At week 18/19, fine movements were normal, whereas TH and GFAP were decreased in the striatum, but not in the substantia nigra. At week 24/25, fine movements were impaired, and TH was decreased both in the striatum and the substantia nigra and S100b was increased in the substantia nigra. Astrogliosis may contribute to the increased brain volume found after BSSG exposure. Using the BSSG model of parkinsonism, the results demonstrate early functional and structural alterations in MRI imaging that occur before the appearance of detectable motor symptoms.