Single prolonged stress: toward an animal model of posttraumatic stress disorder

Abstract

Although selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in decreasing posttraumatic stress disorder (PTSD) symptoms, a subgroup of PTSD patients remain chronically symptomatic and maintain conditioned fear responses to traumatic stimuli. In this context, the establishment of an appropriate animal model of PTSD is necessary to promote better understanding of the mechanisms of the disorder and to facilitate the development of more effective therapeutic alternatives to SSRIs. Although no single widely accepted animal model of PTSD has been established to date, the single prolonged stress (SPS) animal model has been partially validated as a model for PTSD. SPS rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety-like behavior and glucocorticoid negative feedback, and they exhibit the expected therapeutic response to paroxetine on enhanced fear memory. In addition, SPS rats exhibit enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which is alleviated by D-cycloserine. The enhanced consolidation and impaired extinction of fear memory found in SPS rats suggests that this model has additional value because recent studies of PTSD indicate that memory abnormalities are a central feature. In this study, we summarize the behavioral and pathophysiological PTSD-like symptoms in SPS, focusing on memory abnormalities, and evaluate the validity of SPS as an animal model of PTSD.

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

“…A single prolonged stress (SPS) model was employed to simulate PTSD in pregnant rats (Yamamoto et al, 2009). The SPS model was proposed by Israel Liberzon and replicated the specific neuro-endocrinological abnormalities observed in patients with PTSD (Yamamoto et al, 2009).…”

“…The SPS model was proposed by Israel Liberzon and replicated the specific neuro-endocrinological abnormalities observed in patients with PTSD (Yamamoto et al, 2009). Rats in the PTSD group were restrained for 2 h and then immediately underwent forced swimming for 20 min in water (height: 40 cm) at a temperature of 25°C in a plastic tub (diameter: 50 cm, height: 70 cm), with six rats swimming at a time.…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…This model involves the presentation of a complex stressor (restraint, 20 min forced swim and exposure to diethyl ether until consciousness is lost) prior to presentation of fear conditioning. This model has the advantage of representing the multidimensional nature of PTSD and results in enhanced fear conditioning and impaired extinction (Iwamoto et al 2007;Kohda et al 2007;Knox et al 2012), as well as increased fear renewal (Yamamoto et al 2009), exaggerated startle (Khan and Liberzon 2004), enhanced glucocorticoid negative feedback (Liberzon et al 1997;Iwamoto et al 2007), deficits in spatial memory, and stress-induced analgesia (Yamamoto et al 2009). SSRIs can reverse the increase in contextual fear conditioning (Takahashi et al 2006) and DCS (Yamamoto et al 2008) ameliorates the impaired extinction in the SPS model, which gives the model good predictive validity, as these drugs alleviate symptoms in some PTSD patients (Albucher and Liberzon 2002;de Kleine et al 2015).…”

“…Several recent reviews have covered the broad array of neurobiological players that have been found to mediate SEFL, such as glucocorticoids, glutamate, glycine, and cytokines (Cordero et al 2003;Akirav and Maroun 2007;Iwamoto et al 2007;Kohda et al 2007;Yamamoto et al 2009;Tronson et al 2010;Jones et al 2015;Maren and Holmes 2016;Perusini et al 2016). However, in spite of the contribution of epigenetic mechanisms to stress and numerous aspects of fear memory independently, very little work has been done in the realm of epigenetics at the crossroads between stress and fear memory.…”

“…For instance, SPS before fear conditioning results in a delayed extinction profile (Yamamoto et al 2009;Chauveau et al 2012;Sawamura et al 2016), an effect that can be rescued by treatment with an HDAC inhibitor (Matsumoto et al 2013). This is not surprising, given that HDAC inhibitors increase acetylation to support extinction learning and decrease anxiety in animal stress paradigms (Yamawaki et al 2012;Valvassori et al 2014).…”