Psychosocial animal model of PTSD produces a long-lasting traumatic memory, an increase in general anxiety and PTSD-like glucocorticoid abnormalities
Introduction
Individuals exposed to intense, life-threatening trauma are at significant risk for developing post-traumatic stress disorder (PTSD). People who develop PTSD respond to a traumatic experience with intense fear, helplessness and horror (American Psychiatric Association, 1994) and subsequently endure chronic psychological distress by repeatedly reliving their trauma through intrusive, flashback memories (Ehlers et al., 2004, Hackmann et al., 2004, McFarlane, 1992, Reynolds and Brewin, 1998, Reynolds and Brewin, 1999, Speckens et al., 2006, Speckens et al., 2007). These intrusive memories are triggered by cues which were associated with the trauma and can, in extreme cases, lead to panic attacks. Therefore, PTSD patients make great efforts to avoid stimuli that remind them of their trauma. The re-experiencing and avoidance symptoms of the disorder can hinder everyday functioning in PTSD patients and foster the development of additional debilitating symptoms, including persistent anxiety, exaggerated startle, cognitive impairments and diminished extinction of conditioned fear (Brewin et al., 2000, Elzinga and Bremner, 2002, Geuze et al., 2009, Graham and Milad, 2011, Milad et al., 2009, Nemeroff et al., 2006, Newport and Nemeroff, 2000, Stam, 2007).
PTSD is also characterized by an aberrant biological profile in different endocrine and physiological systems (Krystal and Neumeister, 2009, Pervanidou and Chrousos, 2010, Vidovic et al., 2011). One of the most extensively researched endocrine systems in people with PTSD is the hypothalamic-pituitary-adrenal (HPA) axis. Empirical investigations of the adrenal hormone, cortisol, have often reported abnormally low baseline cortisol levels in people with PTSD (for reviews, see Yehuda, 2005, Yehuda, 2009). One explanation for the presence of low baseline cortisol levels in people with PTSD is that trauma induces an enhancement of negative feedback inhibition of the HPA axis. For example, studies have reported that people with PTSD display an increased number and sensitivity of glucocorticoid receptors (Rohleder et al., 2004, Stein et al., 1997, Yehuda et al., 1991, Yehuda et al., 1993a, Yehuda et al., 1995) and an increased suppression of cortisol and adrenocorticotropic hormone (ACTH) following the administration of dexamethasone, a synthetic glucocorticoid (Duval et al., 2004, Goenjian et al., 1996, Grossman et al., 2003, McFarlane et al., 2011, Newport et al., 2004, Stein et al., 1997, Yehuda et al., 1993b, Yehuda et al., 1995, Yehuda et al., 2002, Yehuda et al., 2004). Some studies have also observed greater increases in ACTH levels of PTSD patients, relative to controls, following the administration of metyrapone. This finding may be the result of metyrapone reducing the enhanced negative feedback inhibition present in PTSD patients (Otte et al., 2006, Yehuda et al., 1996).
Studies have also employed the dexamethasone-corticotropin releasing hormone (CRH) challenge paradigm to study abnormal HPA axis functioning in people with PTSD (de Kloet et al., 2006). An advantage of this paradigm is that the subjects are treated with dexamethasone prior to CRH administration, thereby activating negative feedback mechanisms before acute HPA axis stimulation. Studies have generally reported reduced ACTH levels in dexamethasone-treated PTSD patients who were subsequently treated with CRH. These findings support the notion that PTSD patients exhibit reduced sensitivity to CRH stimulation (Rinne et al., 2002, Strohle et al., 2008).
Overall, extensive research indicates that PTSD is characterized by reduced basal levels of cortisol, reduced CRH receptor sensitivity and/or enhanced glucocorticoid negative feedback at the level of the pituitary. However, the literature in this area is not entirely consistent, which likely reflects the heterogeneity in the manifestation of trauma and the measurement of PTSD in different patient populations (Begic and Jokic-Begic, 2007, Bonne et al., 2003, Hamner et al., 2004, Klaassens et al., 2012, Marshall and Garakani, 2002, Metzger et al., 2008, Pitman and Orr, 1990, Radant et al., 2001, Shalev et al., 2008).
Our understanding of how trauma affects the HPA axis in people may be enhanced by animal models that generate PTSD-like behavioral and physiological abnormalities. To this end, we have developed an animal model of PTSD that includes trauma induction procedures which are analogous to those that induce PTSD in people, including a threat to survival, a lack of control, an intrusive re-experiencing of a traumatic event and social instability (Roth et al., 2011, Zoladz et al., 2008, Zoladz and Diamond, 2010). Specifically, our animal model of PTSD is based on a combination of acute traumatic experiences (two 1-h periods of inescapable confinement of rats in close proximity to a cat) embedded within a 1 month-long period of social stress. We reported that rats administered this psychosocial stress regimen exhibited changes in physiology and behavior in common with people diagnosed with PTSD, including heightened anxiety, exaggerated startle, impaired cognition, increased cardiovascular reactivity and an exaggerated response to yohimbine administration (Brewin et al., 2000, Elzinga and Bremner, 2002, Nemeroff et al., 2006, Newport and Nemeroff, 2000, Stam, 2007). Moreover, we recently demonstrated that our psychosocial predator stress model of PTSD produced hippocampus-specific increases in DNA methylation (Roth et al., 2011), a finding which may be relevant toward understanding how traumatic memories can persist for a lifetime (Yehuda and Bierer, 2009).
The purpose of the present experiments was to extend our animal model of PTSD to determine if rats administered psychosocial stress would exhibit two hallmark features of PTSD: (1) a long-lasting memory of the traumatic event (inescapable live cat exposure); and (2) abnormalities in glucocorticoid levels under baseline conditions and in response to stress and dexamethasone administration.
Section snippets
Subjects
Experimentally-naïve adult male Sprague-Dawley rats (225–250 g upon delivery) obtained from Charles River laboratories (Wilmington, MA) were used in all experiments. The rats were pair-housed on a 12-h light/dark schedule (lights on at 0700 h) in standard Plexiglas cages with free access to food and water. The colony room temperature and humidity were maintained at 20 ± 1 °C and 60 ± 3%, respectively. After the rats were given a 1-week vivarium acclimation period, their weights increased to 304 g (±2.3
Growth rates and organ weights
The psychosocial stress group exhibited a significantly lower growth rate, t(17) = 3.43, significantly larger adrenal glands, t(14) = 2.24, and a significantly smaller thymus, t(16) = 2.78, than the no psychosocial stress group (p's < 0.05; Table 1).
Traumatic memory expression
The psychosocial stress group exhibited significantly greater immobility than the no psychosocial stress group during the context test, t(14) = 4.55, p < 0.001. The analysis of the cue test revealed significant main effects of psychosocial stress, F(1,16) = 6.26,
Discussion
The overall goal of our research program has been to develop an animal model of PTSD based on clinically-relevant features of the disorder. To this end, we previously demonstrated that two episodes of inescapable cat exposure, in conjunction with daily social instability, caused rats to exhibit heightened anxiety, exaggerated startle, impaired cognition, increased cardiovascular reactivity and an exaggerated response to yohimbine administration (Zoladz et al., 2008, Zoladz and Diamond, 2010),
Concluding remarks
We have developed an animal model of PTSD that includes trauma induction procedures which are analogous to those that induce PTSD in people, including a threat to survival, a lack of control, an intrusive reminder of a traumatic experience and social instability. Rats administered this psychosocial stress regimen exhibited changes in physiology and behavior in common with people diagnosed with PTSD, including heightened anxiety, exaggerated startle, impaired cognition, increased cardiovascular
Conflicts of interest
All other authors declare that they have no conflicts of interest.
Contributors
David Diamond designed the study and contributed to the editing of the manuscript. Phillip Zoladz contributed to the design of the study, conducted all laboratory procedures and wrote the first draft of the manuscript. Monika Fleshner contributed to the design of the study, conducted the corticosterone assays and contributed to the editing of the manuscript. All authors contributed to and have approved the final manuscript.
Role of the funding source
Funding for this study was provided by the Department of Veterans Affairs; the VA had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
Acknowledgements
This research was supported by Research Career Scientist and Merit Review Awards from the Department of Veterans Affairs to David Diamond.
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