Traumatic brain injury alterations in the functional connectome are associated with neuroinflammation but not tau in a P30IL tauopathy mouse model.

INTRODUCTION: Traumatic Brain Injury (TBI) is often associated with long-term cognitive deficits and altered brain networks which have been linked with accumulation of neurofibrillary tau tangles and neuroinflammation. In this work, we investigated the changes in the brain post-TBI in an Alzheimer's disease pR5 tauopathy model and evaluated the contribution of tauopathy and neuroinflammation to connectivity alterations using resting-state functional Magnetic Resonance Imaging (rs-fMRI). METHOD: 26 P301L tau transgenic mice of 8-9 months of age (21-35 g) expressing the human tau isoform carrying the pathogenic P301L mutation were used for the study. Animals were assessed at day 1 and 7 post-injury/craniotomy and were randomly divided into four groups. All animals underwent an MRI scan on a 9.4T Bruker system where rsfMRI was acquired. Following imaging, brains were stained with pSer (396 + 404), glial fibrillary acidic protein (GFAP), and ionised calcium-binding adaptor molecule-1 (Iba-1). Group-information-guided Independent Component Analysis (GIG-ICA) and region-of-interest (ROI)-based network connectivity approaches were applied. Principal Component Regression was applied to predict connectivity network strength from the corresponding ROIs. RESULTS: TBI mice showed decreased functional connectivity in the dentate gyrus, thalamus, and other areas compared to sham animals at day 1 post-injury with the majority of changes resolving at day 7. Principal Component Regression showed only the contralateral CA1 network strength was correlated with the CA1's astrocyte and microglia cell density and the ipsilateral thalamus network strength was correlated with the ipsilateral thalamus' astrocyte and microglia cell density. CONCLUSION: We present the first report on the temporal alterations in functional connectivity in a P30IL mouse model following TBI. Connectivity between key regions known to be affected in Alzheimer's disease were short-term and reversible following injury. Connectivity strength in CA1 and thalamus showed significant correlation with astrocyte and microglial cell density but not tau density.