Comprehensive behavioral analyses of male and female mice derived from mothers fed a diet high in omega-6 and low in omega-3 fatty acids

Background and objectives: Most animals cannot synthesize omega-6 (n-6) or omega-3 (n-3) polyunsaturated fatty acids (PUFAs), which are essential nutrients for normal brain development and function. These PUFAs are generally competitive in various metabolic processes, and the n-6/n-3 ratio of PUFAs that compose our body warrants particular attention. Regarding recent nutritional trends leading to foods that are high in n-6 PUFAs and low in n-3 PUFAs, we previously reported that intake of an n-6-high/n-3-low diet by pregnant mice induces offspring's enhanced anxiety-related behaviors and hedonic feeding behaviors in adulthood, although the offspring were raised on a well-balanced control diet after birth. This study aims to comprehensively understand the behavioral consequences of the offspring exposed to the n-6-high/n-3-low diet in utero. Methods: Female wild-type mice were fed either the well-balanced control diet or the n-6-high/n-3-low diet, and the mice were mated and maintained on their respective diet through gestation. At the day of birth, the lactating mothers were exposed to a standard lab chow by replacing the control diet or the n-6-high/n-3-low diet. Offspring after weaning were continued to feed the lab chow. Male and female offspring in adulthood were subjected to a comprehensive behavioral test battery including the open field test, elevated plus-maze test, social interaction test, three-chamber social approach test, rotarod test, Porsolt forced swim test, and several learning tests. The offspring's brain fatty acids were also investigated. Results: We newly identified significant behavioral differences between the two dietary groups; both male and female offspring exposed to the n-6-high/n-3-low diet in utero showed a decreased social behavior and an impairment in pattern separation, and female offspring exposed to the n-6high/n-3-low diet in utero showed hyperactivity, compared to those exposed to the control diet in utero. We also confirmed that the brain n-6 and n-3 PUFAs, especially arachidonic acid and docosahexaenoic acid, were increased and decreased, respectively, in the embryos exposed to the n-6-high/n-3-low diet in utero compared to those exposed to the control diet in utero. Conclusions: Our findings show that maternal intake of PUFAs during pregnancy can have long-lasting effects on offspring's various behaviors in adulthood.