Behavior and Brain Gene Expression Changes in Mice Exposed to Preimplantation and Prenatal Stress

Preimplantation culture of mouse embryos has been suggested to result in reduced anxiety-like behavior in adulthood. Here,we investigated the effects of in vitro fertilization (IVF), embryo culture, and different diets on anxiety-like behavior using theelevated plus maze (EPM). We hypothesized that exposure to suboptimal conditions during the preimplantation stage wouldinteract with the suboptimal diet to alter behavior. The expression of genes related to anxiety was then assessed by quantitativereal-time polymerase chain reaction in various brain regions. When fed a normal diet during gestation and a moderatelyhigh-fat Western diet (WD) postnatally, naturally conceived (NC) and IVF mice showed similar anxiety-like behavior on theEPM. However, when fed a low-protein diet prenatally and a high-fat diet postnatally (LP/HF), NC mice showed a modestincrease in anxiety-like behavior, whereas IVF mice showed the opposite: a strongly reduced anxiety-like behavior on the EPM.The robust reduction in anxiety-like behavior in IVF males fed the LP/HF diets was, intriguingly, associated with reducedexpression of MAO-A, CRFR2, and GABA markers in the hypothalamus and cortex. These findings are discussed in relationto the developmental origin of health and disease hypothesis and the 2-hit model, which suggests that 2 events, occurring atdifferent times in development, can act synergistically with long-term consequences observed during adulthood.