Prenatal maternal stress alters depression-related symptoms in a strain - and sex-dependent manner in rodent offspring

Abstract Stress during pregnancy adversely affects foetal development and leads to later behavioural outcomes in offspring. Preclinical studies have reported conflicting effects of prenatal stress on depression-related symptoms in rodent offspring. This study aimed to study the combined effect of strain and sex on prenatal stress outcomes in a single study. To this end, male and female offspring from outbred Wistar and inbred Lewis rats, and outbred NMRI and inbred C57BL6 mice were compared. As outcomes we focussed on depression-related behaviour and related molecular and neurochemical parameters. Prenatally stressed and non-stressed offspring were subjected to the sucrose preference, novelty-suppressed feeding, tail suspension, and forced swim tests. We measured basal and stress-induced corticosterone levels in the serum, and brain-derived-neurotrophic-factor (BDNF), interleukin-1β, tumor necrosis factor-α, glutamate and serotonin in the brain to determine changes in hypothalamic–pituitary–adrenal-(HPA)-axis function, neuroplasticity, neuroinflammation, and neurotransmission. Our findings revealed that prenatal stress increases depression-like behaviour, HPA-axis (re) activity, pro-inflammatory cytokines and glutamate levels, and decreases BDNF and serotonin levels in a strain and sex-dependent manner in rodent offspring. Overall, male and female Lewis rats, female Wistar rats, and female C57BL6 mice were found to be most responsive to prenatal stress. Based on these results, we conclude that genetic background and sex contribute to the great diversity in the effects of prenatal maternal stress in animals.