Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation

Abstract

Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials.

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

“…Anxiety and trauma-related disorders are widespread and costly 5 Comer et al, 2011;Kinley et al, 2011;Salas-Wright et al, 2014;Stein et al, 2017;Wittchen, 6 2002), and remain difficult to treat (Colvonen et al, 2017;Costello et al, 2014;Iza et al, 2013;7 Sinnema et al, 2015). Understanding the neural circuits underlying anxiety is important for 8 refining behavioral and pharmacotherapeutic treatments (Berridge, 2018;Deslauriers et al, 2017;9 Fanselow andPennington, 2018, 2017;Graham et al, 2014;LeDoux and Daw, 2018;Nees et al, 10 2015;Pine and LeDoux, 2017;Tye, 2018). Several recent studies have demonstrated changes in 11 the function of the bed nucleus of the stria terminalis (BNST) in individuals with post-traumatic 12 stress disorder (PTSD) and anxiety disorders (Andreescu et al, 2015;Brinkmann et al, 2018;L 13 Brinkmann et al, 2017;Leonie Brinkmann et al, 2017;Buff et al, 2017;Münsterkötter et al, 14 2015;Rabellino et al, 2018;Straube et al, 2007;Yassa et al, 2012).…”

Inflammation is a stronger predictor of psychological trauma exposure than behavior in repeated social defeat

“…RSDS was performed as previously described. 15 In brief, control and RSDS animals were [8][9][10][11][12] week-old wild-type male mice of a C57BL/6J background (Jackson Laboratory #000664, Bar Harbor, ME, USA). Seventy-four total animals were used in this study.…”

“…10 In attempts to elucidate the pathophysiology of PTSD, many preclinical rodent models have emerged. 11,12 Repeated social defeat stress (RSDS) is a well-characterized murine model that relies upon the aggressive and territorial nature of retired breeder CD-1 mice, 13 while successfully recapitulating several behavioral and inflammatory aspects of PTSD. 11,12 Furthermore, this model has been reported to produce both susceptible and resilient populations as defined by a single parameter on the social interaction behavioral test (i.e., social interaction ratio <1.0 or ≥1.0, respectively).…”

“…11,12 Repeated social defeat stress (RSDS) is a well-characterized murine model that relies upon the aggressive and territorial nature of retired breeder CD-1 mice, 13 while successfully recapitulating several behavioral and inflammatory aspects of PTSD. 11,12 Furthermore, this model has been reported to produce both susceptible and resilient populations as defined by a single parameter on the social interaction behavioral test (i.e., social interaction ratio <1.0 or ≥1.0, respectively). 13,14 Recent work from our group utilized the model of RSDS to examine the autonomic and redox profiles of T-lymphocytes after psychological trauma exposure.…”

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

“…Our study investigated how BNST hyperactivation (as recognized in anxiety disorders) modulates fear learning characteristics in a Pavlovian fear conditioning paradigm that is suitable for translational studies by targeting conserved mechanisms (Deslauriers et al, 2018;Flandreau and Toth, 2018). We investigated different phases of fear learning, i.e.…”