Lei Zhang

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental disorder afflicting more than 7% of the US population and 12% of military service members. Since the Afghanistan and Iraq wars, thousands of US service members have returned home with PTSD. Despite recent progress, the molecular mechanisms underlying the pathology of PTSD are poorly understood. To promote research on PTSD (especially its molecular mechanisms) and to set a molecular basis for discovering novel medications for this disorder, well-validated animal models are needed. However, to develop PTSD animal models is a challenging process, due to predisposing factors such as physiological, behavioral, emotional, and cognitive changes that emerge after trauma. Currently, there is no well-validated animal model of PTSD, although several stress paradigms mimic the behavioral symptoms and neurological alterations seen in PTSD. In this chapter, we will provide an overview of animal models of PTSD including learned helplessness, footshock, restraint stress, inescapable tail shock, single-prolonged stress, underwater trauma, social isolation, social defeat, early-life stress, and predator-based stress. We emphasize rodent models because they reproduce some of the behavioral and biotical phenotypes seen in PTSD. We will also present data showing that homologous biological measures are increasingly incorporated in studies to assess markers of risk and therapeutic response in these models. Therefore, PTSD animal models may be refined in hopes of capitalizing on the understanding of the molecular mechanisms and delivering tools in order to develop new and more efficacious treatments for PTSD.

Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met

Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (PPn=28) or without PTSD (n=31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P=0.0027, false discovery rate (FDR)=0.043) and PPAR (P=0.006, FDR=0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

Posttraumatic stress disorder (PTSD) is a chronic and disabling anxiety disorder that occurs after a traumatic event. It is associated with an increased risk of suicide and marked deficits in social and occupational functioning. Currently, the diagnosis for PTSD is established on the basis of a patient’s clinical history, mental status examination, duration of symptoms, and clinician administered symptom checklist or patient self-report. However, there are no available laboratory biomarker tests for PTSD. To begin intervention at the earliest possible time, priority must be given to developing objective approaches to determine the presence of PTSD. Thus, using cutting-edge technology and skill to develop a simple blood test or a biomarker to detect PTSD at its earliest and most treatable stage would benefit both physician and patient. Several technologies and skills have been used in the identification biomarker research. We discuss three major methods in this chapter (blood RNA and DNA purification, chromatin immunoprecipitation, and Western blot), which have been used in our study to determine whether p11 is a potential biomarker for PTSD. Using these procedures will not only enhance the study of the molecular mechanisms of PTSD but also help the translation of basic science to a clinical setting.