Systematic Review and Methodological Considerations for the Use of Single Prolonged Stress and Fear Extinction Retention in Rodents

Abstract

Posttraumatic stress disorder (PTSD) is a mental health condition triggered by experiencing or witnessing a terrifying event that can lead to lifelong burden that increases mortality and adverse health outcomes. Yet, no new treatments have reached the market in two decades. Thus, screening potential interventions for PTSD is of high priority. Animal models often serve as a critical translational tool to bring new therapeutics from bench to bedside. However, the lack of concordance of some human clinical trial outcomes with preclinical animal efficacy findings has led to a questioning of the methods of how animal studies are conducted and translational validity established. Thus, we conducted a systematic review to determine methodological variability in studies that applied a prominent animal model of trauma-like stress, single prolonged stress (SPS). The SPS model has been utilized to evaluate a myriad of PTSD-relevant outcomes including extinction retention. Rodents exposed to SPS express an extinction retention deficit, a phenotype identified in humans with PTSD, in which fear memory is aberrantly retained after fear memory extinction. The current systematic review examines methodological variation across all phases of the SPS paradigm, as well as strategies for behavioral coding, data processing, statistical approach, and the depiction of data. Solutions for key challenges and sources of variation within these domains are discussed. In response to methodological variation in SPS studies, an expert panel was convened to generate methodological considerations to guide researchers in the application of SPS and the evaluation of extinction retention as a test for a PTSD-like phenotype. Many of these guidelines are applicable to all rodent paradigms developed to model trauma effects or learned fear processes relevant to PTSD, and not limited to SPS. Efforts toward optimizing preclinical model application are essential for enhancing the reproducibility and translational validity of preclinical findings, and should be conducted for all preclinical psychiatric research models.

Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress

“…Enhanced anxiety-like behavior and impaired extinction memory are symptoms observed in male rodents subjected to the SPS procedure (Liberzon and Young, 1997;Kohda et al, 2007;Knox et al, 2012aKnox et al, , 2016Noble et al, 2017;Ferland-Beckham et al, 2021). Consistent with previous results, we found that SPS exposure increased anxiety-like behavior and severely impaired extinction of conditioned fear in male rats.…”

“…Prior work indicates that the SPS protocol induces behavioral and physiological phenomena similar to those observed in PTSD patients (Liberzon and Young, 1997;Blechert et al, 2007;Kohda et al, 2007;Glover et al, 2011;Norrholm et al, 2011;Knox et al, 2016). Although the SPS protocol does not impair extinction or increase anxiety-like behavior in female rats (Keller et al, 2015;Mancini et al, 2021), this procedure has been widely used as an animal model of PTSD (Liberzon and Young, 1997;Knox et al, 2016;Souza et al, 2017;Lisieski et al, 2018;Serova et al, 2019;Su et al, 2019;Ferland-Beckham et al, 2021). In addition to increased anxiety and impaired extinction memory consolidation, rats show increased negative hypothalamic-pituitary-adrenal (HPA) feedback (Knox et al, 2012a(Knox et al, , 2016Han et al, 2014;Liu et al, 2016;Noble et al, 2017;Deslauriers et al, 2018) and altered glucocorticoid receptor expression 7 days after SPS exposure (Liberzon et al, 1999;Wang et al, 2009;Knox et al, 2012b;George et al, 2013).…”

Maternal Separation Induces Sex-Specific Differences in Sensitivity to Traumatic Stress

“…Identifying neurobiological mechanisms via which axis, arousal, and re-experiencing symptoms (Liberzon et al, 1997(Liberzon et al, , 1999Khan and Liberzon, 2004;Kohda et al, 2007;George et al, 2012George et al, , 2015Knox et al, 2012). SPS also is relatively easy to implement and can be adapted in a range of research settings (Ferland-Beckham et al, 2021). However-like many animal models of PTSD-SPS was developed in male animals and the consistent effects observed in these animals are not often observed in female animals (Bowers and Ressler, 2015;Keller et al, 2015;Deslauriers et al, 2018;Pooley et al, 2018a,b).…”

Purinergic P2X7 Receptor-mediated inflammation precedes PTSD-related Behaviors in Rats

“…Although the role of the immune system in the pathophysiology of PTSD is unclear, increasing clinical evidence links increased levels of inflammatory cytokines with PTSD [2,[26][27][28]. In our study, we used a well-studied SPS animal model to examine the role of inflammation in the development of PTSD-like behavior after trauma exposure [29][30][31][32]. The delayed onset of impaired fear extinction and increased anxiety-like behavior induced by the SPS protocol [7,11,33] allowed us to examine changes in inflammation prior to the onset of the PTSD-like phenotype.…”