Rodent models of post-traumatic stress disorder: behavioral assessment

Abstract

Although the etiology and expression of psychiatric disorders are complex, mammals show biologically preserved behavioral and neurobiological responses to valent stimuli which underlie the use of rodent models of post-traumatic stress disorder (PTSD). PTSD is a complex phenotype that is difficult to model in rodents because it is diagnosed by patient interview and influenced by both environmental and genetic factors. However, given that PTSD results from traumatic experiences, rodent models can simulate stress induction and disorder development. By manipulating stress type, intensity, duration, and frequency, preclinical models reflect core PTSD phenotypes, measured through various behavioral assays. Paradigms precipitate the disorder by applying physical, social, and psychological stressors individually or in combination. This review discusses the methods used to trigger and evaluate PTSD-like phenotypes. It highlights studies employing each stress model and evaluates their translational efficacies against DSM-5, validity criteria, and criteria proposed by Yehuda and Antelman's commentary in 1993. This is intended to aid in paradigm selection by informing readers about rodent models, their benefits to the clinical community, challenges associated with the translational models, and opportunities for future work. To inform PTSD model validity and relevance to human psychopathology, we propose that models incorporate behavioral test batteries, individual differences, sex differences, strain and stock differences, early life stress effects, biomarkers, stringent success criteria for drug development, Research Domain Criteria, technological advances, and cross-species comparisons. We conclude that, despite the challenges, animal studies will be pivotal to advances in understanding PTSD and the neurobiology of stress.

Fig. 1. Superimposition of reviewed animal models against validity criteria for animal models of human mental disorders (inner circle), Yehuda and Antelman’s criteria for animal models of PTSD (middle circle), and DSM-5 criteria for PTSD (outer circle).

Validity criteria abbreviations: face validity (FV), construct validity (CV), predictive validity (PV). Yehuda and Antelman’s criteria abbreviations: biological and behavioral sequelae of PTSD (1), dose-dependent (2), lasting symptoms (3), bidirectional (4), interindividual variability (5). DSM-5 criteria abbreviations: physiological reactions to trauma reminders (B), increased avoidance (C), cognitive alterations (D₁), mood alterations (D₂), increased arousal (E₁), concentration problems (E₂), sleep disturbance (E₃), lasting symptoms (F). Behavioral test abbreviations: elevated plus maze (EPM), open field (OF), light-dark box (LDB), Morris water maze (MWM), radial arm water maze (RAWM), fear conditioning / fear extinction (FCFE), novel object recognition (NOR), social interaction (SI), forced swim test (FST), sucrose preference (SP), marble burying (MB), acoustic startle response (ASR), electroencephalogram (EEG). White: not reported. Shaded: reported.