Animal models of post-traumatic stress disorder and novel treatment targets

Abstract

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.

Neurobiological Trajectories Involving Social Isolation in PTSD: A Systematic Review

“…Four out of the eight animal studies [42][43][44][45] used mice as experimental subjects and four studies [46][47][48][49] used rats, divided in socially isolated (experimental) and group-housed animals (controls). Face-validity [33,50] was established in all animal studies, since they phenomenologically resembled the human setting of PTSD with inescapable electric foot shock serving as the most common traumatic experience (male intruder, predator odor, restraint, and forced swimming were, moreover, used in parallel or independently). Construct validity [33,50] was served in terms of the effort to identify common underlying mechanisms with the human disorder, whereas predictive validity [33,50] was present in three of the animal studies [42,44,47] in terms of providing predictions concerning therapeutic responses and novel pharmacological targets.…”

“…Face-validity [33,50] was established in all animal studies, since they phenomenologically resembled the human setting of PTSD with inescapable electric foot shock serving as the most common traumatic experience (male intruder, predator odor, restraint, and forced swimming were, moreover, used in parallel or independently). Construct validity [33,50] was served in terms of the effort to identify common underlying mechanisms with the human disorder, whereas predictive validity [33,50] was present in three of the animal studies [42,44,47] in terms of providing predictions concerning therapeutic responses and novel pharmacological targets. Hippocampal and amygdala involvement was investigated in seven of the studies [42,43,[45][46][47][48][49], the role of the HPA-axis and its products in four studies [45,46,48,49], while the endocannabinoid system in three [44,47,48].…”

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.…”