Thyroid Hormone T4 Mitigates Traumatic Brain Injury via Dynamically Remodeling Cell Type Specific Genes and Pathways

The complex pathology of traumatic brain injury (TBI) remains elusive due to the molecular and cellular dynamics that lead to cognitive impairments and neurological disorders. These complex attributes contribute to the difficulties in the success of TBI therapeutic regimens. Previously, we showed the spatiotemporal effects of TBI as well as the ability of T4 administration to prevent the cognitive impairments induced by TBI. Here, we focus on understanding the mechanism involved in the ability of T4 to prevent the cognitive damage induced by TBI using a systems level approach. Using single cell sequencing of two tissues (hippocampus and frontal cortex) at three stages post injury, we identified astrocytes, microglia, oligodendrocytes, and endothelial cells to be the most affected across both tissues and across timepoints after T4 treatment. We also identified key genes that were reversed after T4 treatment such asMbpandPlp1. Oxidative phosphorylation, immune response, and nervous system related pathways were shown to be affected by T4 treatment. Our systems-level approach allows us to further understand the temporal and spatial dynamic reprogramming by T4 that prevents cognitive dysfunction induced by TBI.