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Mild traumatic brain injury (mTBI), often referred to as concussion, is a major cause of morbidity and mortality worldwide. Sleep disturbances are common after mTBI. Moreover, subjects who develop subjective sleep complaints after mTBI also report more severe somatic, mental health, and cognitive impairment and take longer to recover from mTBI sequelae. Despite many previous studies addressing the role of sleep in post-mTBI morbidity, the mechanisms linking sleep to recovery after mTBI remain poorly understood. The glymphatic system is a brain-wide network that supports fluid movement through the cerebral parenchyma and the clearance of interstitial solutes and wastes from the brain. Notably, the glymphatic system is active primarily during sleep. Clearance of cellular byproducts related to somatic, mental health, and neurodegenerative processes (e.g., amyloid-β and tau, among others) depends in part on intact glymphatic function, which becomes impaired after mTBI. In this viewpoint, we review the current knowledge regarding the association between sleep disturbances and post-mTBI symptoms. We also discuss the role of glymphatic dysfunction as a potential link between mTBI, sleep disruption, and post-traumatic morbidity. We outline a model where glymphatic dysfunction and sleep disruption caused by mTBI may have an additive effect on waste clearance, leading to cerebral dysfunction and impaired recovery. Finally, we review the novel techniques being developed to examine glymphatic function in humans and explore potential interventions to alter glymphatic exchange that may offer a novel therapeutic approach to those suffering from poor sleep and prolonged symptoms after mTBI.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450 epoxygenase enzymes recognized as key players in vascular function and disease, primarily attributed to their potent vasodilator, anti-inflammatory and pro-angiogenic effects. Although EETs’ actions in the central nervous system (CNS) appear to parallel those in peripheral tissue, accumulating evidence suggests that epoxyeicosanoid signaling plays different roles in neural tissue compared to peripheral tissue; roles that reflect distinct CNS functions, cellular makeup and intercellular relationships. This is exhibited at many levels including the expression of EETs-synthetic and -metabolic enzymes in central neurons and glial cells, EETs’ role in neuro-glio-vascular coupling during cortical functional activation, the capacity for interaction between epoxyeicosanoid and neuroactive endocannabinoid signaling pathways, and the regulation of neurohormone and neuropeptide release by endogenous EETs. The ability of several CNS cell types to produce and respond to EETs suggests that epoxyeicosanoid signaling is a key integrator of cell–cell communication in the CNS, coordinating cellular responses across different cell types. Under pathophysiological conditions, such as cerebral ischemia, EETs protect neurons, astroglia and vascular endothelium, thus preserving the integrity of cellular networks unique to and essential for proper CNS function. Recognition of EETs’ intimate involvement in CNS function in addition to their multi-cellular protective profile has inspired the development of therapeutic strategies against CNS diseases such as cerebral ischemia, tumors, and neural pain and inflammation that are based on targeting the cellular actions of EETs or their biosynthetic and metabolizing enzymes. Based upon the emerging importance of epoxyeicosanoids in cellular function and disease unique to neural systems, we propose that the actions of “neuroactive EETs” are best considered separately, and not in aggregate with all other peripheral EETs functions.