Identifying Mechanisms of Stress and Sex Differences That Drive Unique Pathology in Blast TBI
Abstract
Combat and operational stress (COS) can include psychological distress linked to mobilization, family separation, and the anticipation of combat leading to cognitive, emotional, behavioral, and physiological responses of Service Members to stress in combat and military operations other than war. This suggests that Soldiers’ mental states are already affected before ever experiencing actual combat. The neurological effects of stress must be considered an important pre-existing condition when developing appropriate preclinical models of trauma for high-stress occupations. From 2000-2019, 413,858 United States military personnel worldwide experienced a traumatic brain injury (TBI); 82.8% were considered mild, 9.8% moderate, and 2.3% penetrating or severe. Out of 770,000 Veterans of Operation Enduring Freedom/Operation Iraqi Freedom who sought care from a VA Medical Center, nearly 60,000 were evaluated or treated for a TBI-related condition. These Veterans experienced elevated rates of psychiatric disorders such as posttraumatic stress disorder (PTSD), which is seen in 2.2–43.9% of returning Veterans, as well as depression and anxiety. The most common type of military brain injury in Veterans is mild TBI (mTBI) from blast exposure. The complex relations between COS and trauma are poorly understood. There is considerable overlap between PTSD and post-concussive symptoms, namely anxiety, irritability, rapid-onset anger and aggression, impulsivity, attention deficits, depression, substance abuse, and insomnia. Further, recent studies have shown that personnel who sustain TBIs while under high amounts of COS report post-concussive symptoms that are many times more severe than those enduring low amounts of stress at the time of injury. This proposal will address the FY21 TBIPHRP IDA Focus Sub-Areas of Understand and Treat. In the Understand Focus Sub-Area, this proposal will address understanding pre-exposure risk and biological factors contributing to an individual’s response and long-term outcomes following brain injury. This Sub-Area will be assessed by focusing on the role of psychological health conditions prior to injury and exposure to repetitive injury, as well as through assessment of biological factors such as sex. To examine this Focus Sub-Area, we have developed an injury paradigm that includes pre-stressing the animals prior to inducing a repeated blast TBI to represent the pre-existing psychological stress Service Members face in and before combat. As it has been shown that males and females are affected differently by not only stress but also TBI, we will further be assessing biological factors contributing to an individual’s response by using both male and female animals. In the Treat Focus Sub-Area, this proposal will address the need for more effective treatment designs that promote recovery and improve long-term outcomes. This Sub-Area will be evaluated by using RNA sequencing technology to study the amygdala, an area of the brain closely associated with stress, anxiety, and fear. By assessing long-term genetic changes post-injury, we aim to identify novel molecular pathways influencing injury outcomes that were previously overlooked by standard unstressed TBI studies. We hypothesize that exposure to stressful situations prior to a TBI will lead to increased anxiety and fear-related behaviors compared to stress or TBI alone and that sex will further play a role in the behavioral outcomes. To examine this hypothesis, we will be exposing male and female rats to a 3-day, acute stress paradigm representing the frequency and intensity of stressors commonly experienced by military personnel followed by exposure to a repetitive blast TBI. The animals will be randomly assigned an exposure group: stress alone, TBI alone, and unstressed-uninjured controls. This will allow us to assess the behavioral changes associated with stress or TBI alone compared to the control group, as well as assess
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211006
Entities
People
- Pamela VandeVord
Organizations
- United States Army
- Virginia Tech