Pontine pathology mediates common symptoms of blast-induced chronic mild traumatic brain injury

Abstract Diffuse mild traumatic brain injury (mTBI) often leads to persistent post-concussive symptoms (PCS) such as fragmented sleep, yet the brain loci and cellular mechanisms that link injury to disability remain obscure. We tested the hypothesis that repeated blast-induced mTBI provokes a chronic myelinopathy with accompanied microglial response in the pontine reticular formation, a brainstem region that modulates arousal and sleep, and that this pathology statistically mediates persistent PCS burden. Using spatially resolved single cell phenotyping in a mouse model of blast-mTBI, we found that only repeated mTBI established persistent activation of disease-associated microglia and phagocytosis of myelin in the pontine reticular formation. Parallel studies in veterans with repeated blast-mTBI revealed identical microglial nodules on neuropathological exam up to two decades after documented blast injury, while diffusion tensor imaging confirmed a dose-dependent pontine myelin disruption that statistically mediated sleep disturbance and broad PCS. Together, these data identify pontine white matter pathology as both a biomarker and mechanistic driver of chronic PCS after repeated diffuse mTBI, highlighting brainstem microglia and oligodendrocytes as rational therapeutic targets.