Polyunsaturated Fatty Acids (PUFA) Enriched Diet Influences Dynamics of Host Genome and Skin Lipidomics Profile: Implications on Mouse Model Simulating Post‐Traumatic Stress Disorder (PTSD) Features

The health benefits of dietary supplementation with n‐3 polyunsaturated fatty acids (n‐3 PUFA) have long been an active area of research. Our previous in vitro results (PLoS One, 2014) showed that optimum balance of n‐3 and n‐6 PUFA in diets can have enduring benefits on cognition, potentiation and neuroprotection. This result motivated us to test the efficacy of these diets in a mouse model eliciting post‐traumatic stress disorder (PTSD) like symptoms. Mice fed PUFA‐enriched diets appeared to have distinctly oily skin and fur, which motivated us to take a closer look at the skin biology of mice. The skin hosts a large spectrum of lipid profiles which play important roles in cell signaling, nutrient consumption and energy synthesis. Furthermore, the skin lipid composition is vulnerable to traumatic stress (Wondrak, 2016). The consequences of this stress include accelerated aging and impaired host defense, which are some of the key symptoms of PTSD. To test this hypothesis, we investigated the interaction between the host transcriptomic and the skin lipidomic profiles to elucidate the long term interaction of PUFA‐enriched diets on PTSD symptoms. Briefly, a customized n‐3 PUFA‐enriched diet (ERD, n3:n6= 7:1), a balanced diet (BLD, n3:n6=1:1) and a standard lab diet (STD, n3:n6= 1:6) were equicaloric and had similar textures and features. These diets were administered separately to three groups of C57BL/6j male mice from their weaning age until late adolescence. Afterwards, the mice were recruited as either subjects or controls (C) in an Aggressor‐Exposed Social Stress (Agg‐E SS) model. Agg‐E mice were cohoused inside an Agg's home‐cage for 6h/d over a 10d period with brief and random direct exposures. C had no Agg interaction. During the 6h schedule, Agg‐E and C mice were food and liquid deprived. After 10d of Agg‐E SS, their behavioral profiles were examined after either a 1d or 4w delay using a contextual cue paradigm. Compared to the STD‐fed mice, both ERD‐ and BLD‐fed mice displayed resilience to stress. In contrast, STD‐fed mice manifested a perturbed behavioral cluster simulating PTSD‐like symptoms such as escalated freezing and grooming, and reduced vigilance. At the end of the 4w rest period, liquid chromatography mass spectrometry (LC‐MS) ‐based lipidomics profiling of the skin lipids was conducted along with transcriptomic analysis of skin mRNA. A significant difference between the C and Agg‐E mice was persistent in all diet groups 4w post Agg‐E SS suggesting a long term relationship between dietary supplements and PTSD symptoms. Interestingly, some of the skin‐specific age markers such as tyrosine and inosine were significantly expressed only in STD Agg‐E SS mice. Integration of these readouts with transcriptomic data and co‐enriched functional analysis elucidated the host‐lipidomics interactions. Additional study is necessary to confirm the findings and derive novel therapeutic mechanisms. Disclaimers Research was conducted in compliance with the Animal Welfare Act, and all other Federal requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.