Understanding how diffuse mild traumatic brain injuries can provoke common and persistent post-concussive symptoms (PCS), such as impaired sleep, is crucial to prevent and treat chronic disability and neurodegeneration. We mapped the spatially-resolved single cell landscape of diffuse mTBI pathology in a mouse model of blast exposure; identifying brainstem injuries predictive of later PCS. Repeated mTBI was necessary to establish chronic microglial activation and phagocytosis of myelin in the pontine reticular formation; where IL33 release by oligodendrocytes predicted microgliopathy. In postmortem brainstem tissues from patients with traumatic brain injury, chronic microglial activation and myelin phagocytosis was evident up to 20 years after diffuse mTBI caused by blast. In living patients with chronic blast mTBI, myelin injury in pontine projections mediated sleep disturbance and other PCS, with a dose dependent effect of mTBI number on sleep disturbance severity. These results support a mechanism for diffuse mTBIs to cause delayed persistent PCS.

The authors have declared no competing interest.

This study was supported by the Veterans Affairs Office of Biomedical Laboratory Research and Development (JSM, I01BX004896; DGC, I01BX002311; AGS, 1IK2BX003258), VA Rehabilitation Research and Development (ERP, I01RX000521, I01RX001612, I01RX003087), VA Puget Sound R and D Seed grant (JSM), University of Washington Friends of Alzheimers Research (DGC, ERP), UW Royalty Research Fund (DGC), and the Northwest Network Mental Illness Research, Education, and Clinical Center (JSM, MAR, ERP). Human brain tissue specimens were derived from the Uniformed Services University neuropathology repository (DP), University of Washington BioRepository and Integrated Neuropathology (BRaIN) Laboratory with support from the Nancy and Buster Alvord Endowment (to CDK), the Henry Jackson Foundation, and the Neuropathology Core of the UW Alzheimers Disease Research Center (P30 AG066509). Authors or their institutions did not, at any time, receive payment or services from a third party for any aspect of the submitted work.

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The Institutional Review Board of the VA Puget Sound Health Care System (Seattle, WA, USA) waived ethical approval of this work.

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