Prenatal Stress-induced Spatial Memory Deficit in a Sex-specific Manner in Mice: A Possible Involvement of Hippocampal Insulin Resistance

Introduction: In the present study, the effects of prenatal stress on spatial learning and memory deficit and its relationship with hippocampal insulin resistance were examined in male and female offspring.

Methods: Female NMRI mice were mated with males overnight, and the 0-day of pregnancy was detected (Gestational day 0-GD0). The pregnant mice were then randomly divided into stress and control groups. The stress group received stress from the GD0 to GD10. On post natal day 30 (PND30), the offspring were divided into 4 subgroups, namely: male-control, female-control, male-stress, and female-stress. Barnes maze method was used for spatial learning evaluation. Plasma cortisol and insulin levels were measured at the beginning of the experiments. At the end of the experiments, the animals' brains were removed, and their hippocampus was extracted. The hippocampus was homogenized, and its insulin and insulin-receptor contents were evaluated.

Results: The stressed animals needed more time for reaching to target hole. In addition, they spend more distance to find the target hole, which was more pronounced in the male offspring. Both plasma and hippocampal insulin content were reduced in the stressed groups. Moreover, the hippocampal insulin receptors protein was reduced in the stressed animals. There was a positive relationship between plasma and hippocampal content and memory deficit in the stressed groups.

Conclusion: These results indicated that prenatal stress could induce spatial learning and memory deficit in offspring, which is associated with plasma and hippocampal insulin and receptor content reduction (hippocampal insulin resistance) in these animals.

Highlights: Maternal stress is very harmful for fetus.The effect of stress is significant during the early days of gestation.This effect is due to several hormonal and neuronal disturbances including Insulin resistance.The effects of stress on the fetus is gender dependent.

Plain language summary: The possible effectiveness of prenatal stress on learning and memory in neonates and also the changes in hippocampus as of essential part of the brain involved in learning and memory. We found that prenatal stress can reduce the insulin effects in hippocampus and it may be the main cause of stress on neonatal memory deficits.