Advancement Of A Valid Model Of Chronic PTSD And Repetitive mTBI: Implications For Pathophysiology And Drug Discovery

Post-traumatic stress disorder (PTSD) is increasingly being recognized as a health and economic burden. PTSD can develop after witnessing or experiencing severe or life threatening trauma and is associated with a number of devastating symptoms that result in decreased quality of life. In addition, PTSD patients have difficulties integrating into society and are at greater risk for other neuropsychiatric disorders, including suicide and substance abuse. The prevalence of PTSD ranges from 8% to 12 % in the general population with a noticeably higher incidences in the US military (20 % -34 %). Current treatment strategies for PTSD are limited and provide only symptomatic relief. Furthermore, many military-related PTSD cases are complicated with the presence of other comorbidities such as mild traumatic brain injury (mTBI). Comorbid PTSD and mTBI pose particular challenges clinically; the similar symptomatic profiles and unclear presentations in the comorbid condition make it difficult to both diagnose and treat. As both military and civilian populations are increasingly exposed to traumatic stress and mTBI, establishing criteria that facilitate the discrimination between these conditions and developing new effective treatments should be a top priority. Animal models are an appropriate platform for conducting such studies. In Chapter 1, the epidemiology, diagnosis and pathophysiology of PTSD and TBI are reviewed. In addition, a quick summary of preclinical animal models of the two conditions is presented. The thesis then focuses on the establishment and validation of a chronic mouse model of PTSD (Chapter 2) and PTSD with comorbid repetitive mild TBI (Chapters 3). Chapter 4 investigates the key molecular mechanisms implicated in PTSD pathophysiology in a mouse model. Finally, the outcomes of a pilot treatment study are presented in Chapter 5.