An estimated 20-30% of people exposed to traumatic events develop post-traumatic stress disorder (PTSD), and 1.64 million US troops have been deployed in guerilla-type combat (Operations Enduring Freedom and Iraqi Freedom) that have a high level of unpredictable and recurring exposures to traumatic events. Thus, it is not surprising that PTSD inflicts rising costs to the Veteran's Administration and society, in general, due to loss of productivity and quality of life. The VA costs associated with paying PTSD-related disability have been steadily rising since 1999, and the treatment costs for personnel with PTSD returning from combat in 2005 were estimated to be nearly $205 million. It is clear that decreasing the number of veterans requiring treatment for PTSD would decrease VA costs associated with this disorder, not to mention increasing the quality of life for many veterans. Importantly, a previous history of PTSD or other anxiety disorders renders some people more susceptible to developing PTSD after subsequent traumatic events. Therefore, the large number of veterans with PTSD or with PTSD susceptibility, are more likely to develop PTSD when they experience non-combat trauma, such as auto accidents, assault, and natural disasters. Therefore, identifying susceptibility and ways to prevent it could decrease PTSD-associated VA costs. Understanding the risk factors for developing PTSD can help reduce the probability of occurrence after experiencing emotional trauma. The goal of this grant is to investigate whether altered hippocampal function is a risk factor or a consequence of experiencing a traumatic event that leads to a PTSD-like behavioral phenotype. If it is a risk factor, as our preliminary data suggest, it can be used as a neurofunctional marker of susceptibility. In these investigations, we will apply two indispensable tools. The first is a novel behavioral model we recently developed to pre-classify rats as susceptible or resistant to developing a PTSD-like phenotype (impaired extinction, lasting elevated startle response) before they experience emotional trauma (fear conditioning). The second tool is the sensitive cellular imaging method, co-developed by the PI, which can assess both size and overlap of neuronal ensembles activated by two distinct behavioral events.
Aim 1 will investigate whether expression of plasticity-associated immediate-early genes, Arc and Homer 1a, in the hippocampal system is altered in susceptible compared to resistant rats before experiencing a traumatic event, as will be predicted if altered hippocampal function is a risk factor and not a consequence of PTSD. Size and overlap of ensembles activated by each of two exploration events will be assessed, along with neuronal density. A second experiment will test whether altered hippocampal function can lead to PTSD-like behaviors by attenuating Arc/H1a expression in resistant rats and then testing their fear extinction and lasting elevation in acoustc startle.
Aim 2 will test whether altered encoding of a traumatic event, at the neural systems level, is part of the pathophysiology of a PTSD-like phenotype by assessing Arc/H1a expression in susceptible and resistant rats after they experience emotional trauma.
Aim 3 will test whether the PTSD-like phenotype of susceptible rats can be reversed with 'cognitive exercise'known to engage the medial prefrontal cortex and hippocampus. Combined, this work will make fundamental discoveries about the role of the hippocampal system in the etiology of PTSD. The finding will inform future studies of how to design objective, within-subject tests for susceptibilty that will not depend on self-reporting and may be used as a supplemental tool in diagnosing PTSD. Findings from Aim 3 will suggest investigating treatments to confer resilience that have a high compliance rate, as they will be low-stress.
The VA has seen a sharp increase in both number of cases with post-traumatic stress disorder (PTSD) and costs associated with PTSD treatment and payment of benefits, which increased from $1.7 to 4.3 billion in the period from 1999-2004. Considering that PTSD is resilient to treatment and that previous traumatic events (with or without PTSD) increase probability of developing PTSD after a subsequent traumatic event, identifying a neurofunctional signature of susceptibility to developing a behavioral and physiological profile associated with PTSD and other anxiety disorders has great potential to decrease loss-of-productivity costs associated with developing PTSD in veterans, regardless of existing PTSD history, and increase the quality of life for many veterans. This grant applies a multilevel approach, which includes techniques developed by the PI, to identify a neurofunctional signature for susceptibility to PTSD-like behaviors in an animal model.