Impact of predatory threat on fear extinction in Lewis rats

Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD.Following a severe traumatic event, some individuals manifest a syndrome, known as post-traumatic stress disorder (PTSD), characterized by repeated painful recollection of the trauma, avoidance of trauma reminders, intrusive thoughts, startle, hyperarousal, and disturbed sleep. Lifetime prevalence of PTSD ranges from 1.4% to 11.2% in representative samples (Afifi et al. 2010). Review of heritability studies indicate that there is a significant genetic component to PTSD (Nugent et al. 2008) as shared genes explain approximately 25%–38% of variability in PTSD symptom clusters and total symptoms (Afifi et al. 2010). Moreover, PTSD heritability coincides with that of other psychiatric conditions such as generalized anxiety, panic disorder, and depression (Chantarujikapong et al. 2001; Fu et al. 2007), suggesting that these disorders gain expression through common biological pathways.Although our understanding of PTSD has improved recently, we still have a limited grasp of the factors that predispose some to be at risk for PTSD, as well as those contributing to PTSD expression following trauma. In part, this situation results from the ethical limitations associated with human studies. For example, humans cannot be randomly assigned to trauma, and, importantly, the invasive techniques required to study the pathophysiology of PTSD can be used only in animals. Thus, a promising approach toward understanding the underlying pathophysiology of PTSD would be to study the disease in a valid animal model of the human syndrome.Fortunately, much work has already been performed to define an animal model of PTSD that reproduces the salient features of the human syndrome (see Adamec et al. 2006; Cohen et al. 2006a; Siegmund and Wotjak 2006). The most promising research has focused on the impact of exposing rodents to species-relevant threatening stimuli that mimic the kind of life-and-death circumstances that precipitates PTSD in humans. Indeed, rodents exposed to predators or their odor develop long-lasting (3 wk or more) manifestations of anxiety as seen in a variety of behavioral assays including the elevated plus maze (EPM), social interaction test, and acoustic startle (Adamec and Shallow 1993; Blanchard et al. 2003; Adamec et al. 2006). The inherent strength of this species-relevant stimulus was demonstrated in studies where predator odor served as an unconditioned stimulus to support cued or contextual fear conditioning (Blanchard et al. 2001; McGregor et al. 2002). As is the case with human PTSD, differential vulnerability to predatory threat was also observed in rodents. In one study, for instance, the propensity of different strains of rats to develop extreme behavioral manifestations of anxiety (EBMAs) as a result of predatory threat has been characterized, revealing that a much higher proportion (50%) of Lewis rats (an inbred strain) develops EBMAs as a result of an intense predatory threat compared with 10% of Fisher rats and 20% of Sprague–Dawley rats (Cohen et al. 2006b).Although these results are promising, it remains unclear whether Lewis rats also exhibit traits that parallel the pathophysiology of human PTSD. One such factor, thought to play a particularly critical role in the persistence of PTSD, is a compromised ability to extinguish fear memories (for review, see Quirk and Mueller 2008). Two main lines of evidence support this notion. First, in functional imaging studies, the brain structures that normally support fear expression and extinction (for review, see Pape and Pare 2010) show abnormal activity patterns in PTSD (Rauch et al. 2006; Shin et al. 2006; Bremner et al. 2008; Milad et al. 2009). Second, several studies have reported that individuals with PTSD are deficient at extinguishing classically conditioned fear responses (Orr et al. 2000; Peri et al. 2000; Blechert et al. 2007; Milad et al. 2008, 2009). Of particular interest, a study of identical twins discordant for trauma exposure has revealed that this extinction deficit was not a pre-existing condition but developed as a result of trauma (Milad et al. 2008). Given the possibility that an inability to extinguish fear might contribute to the maintenance of PTSD, we therefore tested whether Lewis rats reproduced the properties of extinction seen in human PTSD.