Long-term molecular differences between resilient and susceptible mice after a single traumatic exposure.

Abstract

Post-traumatic stress disorder (PTSD) is a heterogeneous disorder induced by trauma, resulting in severe long-term impairments of an individual's mental health. PTSD does not develop in every individual and, thus, some individuals are more resilient. However, the underlying molecular mechanisms are poorly understood. Here, we aimed to elucidate these processes. We used a single-trauma PTSD model in mice to induce long-term maladaptive behaviours and profiled the mice 4weeks after trauma into resilient or susceptible individuals. The classification of phenotype was based on individual responses in different behavioural experiments. We analysed microbiome, circulating endocannabinoids, and long-term changes in brain phospholipid and transcript levels. We found many molecular differences between resilient and susceptible individuals across multiple molecular domains, including lipidome, transcriptome and gut microbiome. Some differences were stable even several weeks after the trauma, indicating the long-term impact of traumatic stimuli on the organism's physiology. Furthermore, the integration of these multilayered molecular data revealed that resilient and susceptible individuals have very distinct molecular signatures across various physiological systems. Trauma induced individual-specific behavioural responses that, in combination with a longitudinal characterisation of mice, could be used to identify distinct sub-phenotypes within the trauma-exposed group. These groups differed significantly not only in their behaviour but also in specific molecular aspects across a variety of tissues and brain regions. This approach may reveal new targets and predictive biomarkers for the pharmacological treatment and prognosis of stress-related disorders. This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.