The Role of Microglia in Sleep Disturbances Following a Traumatic Brain Injury
Abstract
Background: Traumatic brain injury (TBI) affects approximately 2.5 million people in the United States each year, with a significantly higher incidence among active-duty military and Veterans. An estimated >50% of TBI survivors experience post-injury sleep disturbances, including insomnia, hypersomnia, obstructive sleep apnea, and circadian rhythm disorders. The high prevalence of post-traumatic stress disorder (PTSD) in military personnel with brain injuries further increases the susceptible of TBI survivors to sleep disorders. Furthermore, military operations often involve acute sleep deprivation and military personnel experience a high prevalence of chronic sleep deficiency during active duty. Insufficient sleep induces inflammation and exacerbates subsequent sleep disturbances and functional outcomes following a TBI. Untreated sleep disturbances impede recovery and translate to longer hospital stays, higher cost of rehabilitation, more physical and psychological disabilities, and a delay in return to work. Despite recent attention, sleep is understudied in the Veteran population. Few treatments and rehabilitation protocols target sleep, though poor sleep remains at clinical levels and continues to adversely impact functioning even after the resolution of other TBI symptoms. Rationale: Sleep is vital to physical and mental health, and is disrupted by inflammatory insult, including pathogens and cellular damage. Inflammation modulates sleep and conversely sleep, or sleep loss, alters inflammatory responses, including production of inflammatory cytokines that modulate sleep. A trigger, such as a TBI, initiates the innate immune response in the brain through the activation of microglia. Microglia activated by TBI can become dysregulated and produce high levels of inflammatory cytokines, which amplify and prolong the inflammatory response, hinder central nervous system repair, and exacerbate neurological symptoms such as inflammation-induced sleep disturbances. Although the role of microglia in the immune response has been exhaustively studied, the role of microglia in inflammation-induced sleep disturbances and resulting sequelae remains unknown. Thus, a critical need is to determine the biological mechanisms through which sleep disruption prior to TBI, and microglia dysregulation following brain injury, may contribute to inflammation-induced sleep disturbances and other sequelae (e.g., impaired cognition). Objectives and Hypothesis: Our long-term objective is to identify mechanistic links between inflammation and sleep that could be used to track therapeutic windows and identify pharmacological targets in the delivery of personalized healthcare. Our prior research and preliminary data demonstrate that a diffuse TBI induced by midline fluid percussion injury (mFPI) acutely alters sleep of male and female mice, which is temporally associated with microglia activation and increased central and peripheral inflammation. We have also shown pharmacologically targeting inflammatory pathways prevents this acute increase in sleep and improves functional recovery in mice following diffuse TBI. Our preliminary data demonstrate that microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) for their survival. We reported that the use of a highly selective CSF1R inhibitor (PLX5622) depletes microglia (to <0.5% of control levels) without changing baseline sleep-wake behavior or the robustness of wake-related behavior; central cytokine concentrations; or functional outcomes in mice. On the basis of these collective data, we hypothesize that microglia mediate brain injury-induced inflammatory responses and consequent neurological impairments, such that microglia depletion will reduce inflammation-induced sleep disruption (consolidate, improve sleep quality), attenuate inflammation, and preserve neurological function. We also hypothesize that sleep disruption prior to TBI worsens inflammation and functional outcomes, and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210384
Entities
People
- Mark R. Opp
Organizations
- United States Army
- University of Colorado Boulder