Thyroid Hormone T4 Mitigates Traumatic Brain Injury by Dynamically Remodeling Cell Type Specific Genes, Pathways, and Networks in Hippocampus and Frontal Cortex

The complex pathology of traumatic brain injury (TBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Previously, we showed that thyroxine (T4) administration prevented the cognitive impairments induced by TBI in mice. To understand the underlying mechanism, we carried out a systems level single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages. Our multi-tissue multi-stage results showed that acute T4 treatment within 6 hours of injury altered the transcriptome in numerous cell types across tissues and timepoints, in particular in astrocytes, microglia, oligodendrocytes, and endothelial cells. We also identified key TBI-affected genes such as Mbp and Plp1 as well as numerous pathways such as oxidative phosphorylation, immune response, and nervous system related pathways to be reversed after T4 treatment. Within- and between-cell-type network modeling revealed that certain dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in both tissues that were affected by TBI and were mitigated by T4. Integration of the genes altered by TBI and/or T4 with candidate genes from human genome-wide association studies (GWAS) of various diseases support the relevance of T4 treatment in alleviating cognitive, psychiatric and neurodegenerative disorders related to TBI. Our systems-level approach elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications through which T4 mitigates cognitive dysfunction induced by TBI. Overall design: Nine groups of mice (n=7/group) including sham, mTBI, and mTBI+T4 treatments across 24hr, 7-day, and 21-day timepoints were investigated. Mice from the 7-day timepoint underwent spatial learning and memory evaluation using the Barnes Maze. The hippocampus and frontal cortex tissues of a subset of mice from each of the 9 groups (n=3/group) were then subject to scRNAseq analysis.