Single Cell Molecular Alterations Reveal Pathogenesis and Targets of Concussive Brain Injury

The complex neuropathology of traumatic brain injury (TBI) is difficult to dissect in the hippocampus considering the convoluted hippocampal cytoarchitecture. As a major casualty of TBI, hippocampal dysfunction results in cognitive decline that may escalate to other neurological disorders, and the molecular basis is hidden in the genomic programs of individual hippocampal cells. Using the unbiased single cell sequencing method Drop-seq, we uncovered the hippocampal cell types most sensitive to concussive mild TBI (mTBI) as well as the vulnerable genes, pathways and cell-cell interactions predictive of disease pathogenesis in a cell-type specific manner, revealing hidden pathogenic mechanisms and potential targets. Targeting Ttr, encoding the thyroid hormone T4 transporter transthyretin, mitigated the genomic and behavioral abnormalities associated with mTBI. Single cell genomics provides unique evidence about altered circuits and pathogenic pathways, and pinpoints new targets amenable to therapeutics in mTBI and related disorders.