Persistent Hypersomnia Following Repetitive Mild Experimental Traumatic Brain Injury: Roles of Chronic Stress and Sex Differences

Abstract

ABSTRACTTraumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can support proper evaluation and care for patients experiencing persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that can impact long term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a variable sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on five days at 24-hour intervals. TBI components were either five linear force impacts, or a novel alternating repetitive mild TBI (Ar-mTBI) model of linear and rotational (CHIMERA) impacts over five days to produce diffuse pathology. In males and females, UCMS induced anxiety without depressive behavior. Persistent hypersomnia, specifically increased sleep during the active dark period, was found through 6-12 month time points in male mice receiving UCMS with repetitive blast plus TBI events, or surprisingly after UCMS alone. Sleep-wake dysfunction was not found with TBI events alone and was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia is similar to excessive daytime sleepiness reported in patients, which may inform treatments.