Use of the arousal-based individual screening model for studying post-traumatic stress disorder: Findings and future directions

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition arising in a subset of trauma-exposed susceptible individuals, yet the pathophysiological determinants of this individual variability remain largely unresolved. We developed the arousal-based individual screening (AIS) model with the aim of filling key gaps in the preclinical field. The AIS model identifies susceptible and resilient mice of both sexes by applying z-normalization of post-trauma changes in acoustic startle reactivity (ASR) induced by a single 24-hour restraint. Susceptible mice develop a long-lasting, multi-domain PTSD-like phenotype with behavioral abnormalities persisting for at least 75 days post-trauma. Critically, trauma susceptibility rates are sex-dependent: approximately 25–35% in males and 35–45% in females, recapitulating clinically observed sex differences in PTSD prevalence. The AIS model shows face, construct, and predictive validity, including pharmacological response to chronic paroxetine in susceptible animals. Since its establishment, we have used the AIS model to investigate three major pathophysiological dimensions of PTSD susceptibility: epigenetic regulation via brain-region-specific miRNA dysregulation; gut-brain axis dysfunctions, and sex-dependent hippocampal pathophysiological mechanisms. This review synthesizes these findings in relation to the human PTSD phenomenology, argues for the necessity of developing genuinely translational animal models that capture individual variability and sex differences as key experimental variables, and discusses the methodological and ethical considerations surrounding the use of traumatic procedures in preclinical research.