November, 2008
Medial Prefrontal Cortex and HPA Axis Roles, in Generation of PTSD-like Symptoms, In SPS Model
U-M Depression Center Member Israel Liberzon, M.D. was recently awarded a grant to study the symptoms of post traumatic stress disorder using animal models. The grant was awarded by the United States Department of Defense and the United States Army, and was given in the amount of $744,176.
The overall aim of this research project is to investigate stress induced changes in neural processes that lead to aberrant psychological processes. Increasing our understanding of stress induced changes in psychological processes will aid our understanding of psychiatric disorders such as post traumatic stress disorder (PTSD). This in turn should lead to better treatments for PTSD.
To accomplish our aim it is best to use animal models because direct manipulation of experimental parameters is possible and causality can be tested. PTSD’s clinical manifestation include, amongst others, three key sets of symptoms that lead to significant disability and poor overall functioning: the recurrent and intrusive recollections of the traumatic event, avoidance of normal social interactions, and the perception that emotions like fear, anger, and anxiety are beyond the control of the patient (i.e. deficit in regulation of aversive emotions). Neurobiological research has implicated abnormalities in medial prefrontal cortical function centrally, as well as altered hypothalamus-pituitary-adrenal (HPA) axis function in PTSD however; mechanisms that link PTSD symptom generation, medial prefrontal cortical function, and stress axis abnormalities have not been established.
In the last decade Liberzon’s laboratory has developed an animal model of PTSD that induces PTSD specific, HPA axis changes, and behavioral arousal characteristic of PTSD in rodents: Single Prolonged Stress (SPS). Recent preliminary data strongly suggests that SPS induces deficits in extinction, avoidance of social interactions, and deficits in modulation of aversive responses (emotional regulation). This offers an outstanding opportunity to study potential neurobiological mechanisms involved in the generation of a key set of PTSD symptoms in valid animal models.
Dr. Liberzon and colleagues will investigate the neurobiological bases of SPS induced deficits in extinction, avoidance of social interactions, and deficits in modulating aversive responses; as models of intrusive memories, social avoidance, and emotional dysregulation symptoms in PTSD. Their general hypothesis is that SPS induced deficits in these PTSD-like symptoms are caused by the effect SPS has on HPA and medial prefrontal cortical function. They will test this general hypothesis by evaluating the following specific aims: #1): Examine the roles of altered mPFC function and expression of brain glucocorticoid receptors in the development of SPS induced extinction deficits (as a model of PTSD intrusive symptom cluster). # 2): Examine the roles of altered mPFC/amygdala function and of HPA/glucocorticoid receptor function in the development of SPS induced avoidance of social interactions (as a model of PTSD social avoidance cluster). #3): Examine the role of altered mPFC/amygdala function and of altered HPA/glucocorticoid function in the development of SPS induced deficits in defensive behavior regulation (as a model of emotional dysfunction in PTSD).# 4):Examine the ability of SSRI and antikindling drug administration to alleviate SPS induced extinction deficit, social avoidance, and defensive behavior regulation deficits; and the role of mPFC/amygdala function and HPA/glucocorticoid function in this process.
The primary contribution of this research project is to add to the current understanding of PTSD. Many conceptualizations of PTSD focus on either changes in arousal induced by stress or stress induced changes in recall and re-experiencing of the initial traumatic event. The results of this research study will draw attention to another aspect of PTSD that is often overlooked and demonstrate that the effects of stress on psychological function are not limited to changes in arousal or re-experiencing. Liberzon and colleagues will also determine if a certain class of drug (i.e. mood stabilizers) is effective in alleviating emotional regulation dysfunction characteristic of PTSD.
