Current status of animal models of PTSD: behavioral and biological phenotypes and future challenges in improving translation

摘要

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 heterogeneous disorder with 20+ symptoms. Clinical research is increasingly utilizing objective biological measures (e.g. imaging, peripheral biomarkers) or non-verbal behaviors/physiological responses to complement verbally reported symptoms. This shift toward more objectively measurable phenotypes enables refinement of current animal models of PTSD, and supports 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- and/or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to chronic SSRIs. Although a few paradigms probed fear conditioning/extinction and/or utilized peripheral immune, sleep, and non-invasive imaging measures, which we argue should be incorporated more to enhance translation. There was little data in females, at different ages across the lifespan, or on temporal trajectories of phenotypes post-stress, which would inform model utility and experimental design for treatment studies. 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 will support translation of drug efficacy not only from animal models to clinical trials, but potentially improve predictability of stageII for stageIII clinical trials.