UCLA

Post-Traumatic Stress Disorder (PTSD) is a complex, multi-faceted disease that affects a subset of individuals who undergo a traumatic experience. To understand the variety of psychological symptoms and their underpinning neural mechanisms, our laboratory has developed a rodent model of the disease in which animals experience an acute traumatic experience (15 unsignaled footshocks) that leads to a variety of changes in fear, anxiety, and depression (PTSD-like phenotypes). Through using a behavioral model of the disease, we can use pharmacological, behavioral, or genetic manipulations to dissect the neural mechanisms underlying the variety of changes in behavior seen following the acute stressor. In this dissertation, I seek to understand how these different symptoms (exaggerated subsequent fear conditioning, anxiety, and depression) manifest selectively and are driven by distinct neural mechanisms, each of which are sensitive to the effects of stress. As we begin to disentangle the variety of changes that occur in the brain following stress and how these changes in the brain manifest behaviorally, we can ultimately hope to better diagnose and treat individuals who are suffering from the debilitating symptoms associated with PTSD.

In Chapter 2, I test for the effects of pair housing animals prior to, during, and following the acute stressor. Rodents are extremely social animals, and isolation housing has been shown to magnify or sufficiently cause effects of stress. Therefore, it was critical to understand whether isolation housing is necessary for developing the PTSD-like symptoms observed after an acute stressor. Interestingly, I found that housing condition (isolation versus pair) had no effect on subsequent fear and anxiety phenotypes in adult, male rats undergoing an acute stressor.

In Chapter 3, I test for the role of kappa opioid receptors (KORs) in the subsequent expression of PTSD-like phenotypes following an acute stressor. The KOR antagonist JDTic was administered immediately after trauma, then animals were tested for exaggerated fear conditioning, and anxiety and depression assays. JDTic administration did not perturb the enhanced fear conditioning phenotype observed following stress, but it did mitigate anxiety behavior on the elevated plus maze (EPM). JDTic administered to stressed animals caused an increase in time spent in the open arms of the EPM across an 8 minute session. Shockingly, JDTic administered to unstressed animals caused an anxiogenic phenotype as seen by a failure to habituate to the EPM across an 8 minute session. Animals were also tested in the open field test and forced swim test, but there was no effect of JDTic on these measures. Together, these data indicate that KORs have a selective role in the anxiety-like phenotypes seen in rats following an acute stressor. These data are one example of how different neural circuits could contribute differentially to the array of phenotypes observed following acute stress.

In Chapter 4, I use a variety of techniques to assess the neural mechanisms underlying the enhanced fear phenotype observed in our PTSD model. Specifically, I test for changes in excitatory receptors expressed in brain regions associated with fear and anxiety through Western blotting, RT-PCR, and a genetic manipulation to test the contribution of NMDA-R’s to the sensitized fear response. Taken together, these studies begin to describe the neural and molecular changes that lead to the robust enhancement in subsequent fear conditioning observed in stressed animals.

Collectively, these studies serve as a beginning of exploring the many behavioral and neural mechanisms underlying our rodent model of PTSD. Future and subsequent studies may build off of this work to further characterize the PTSD-like phenotypes of our model, and relate these behavioral changes to the specific neural changes that guide them.