Prenatal N-acetyl-cysteine administration prevents social anxiety and modulates brain immune- and plasticity-related genes in adolescent offspring born from high-fat diet C57Bl6/N mouse dams

Aims Maternal obesity is associated to increased oxidative stress (OS) representing a risk factor for adult mental health however the mechanisms underlying the negative long-term effects are poorly understood. We investigated inflammation, OS and hypothalamic-pituitary-adrenal (HPA) axis function in a mouse model of maternal high-fat diet (HFD) as potential mechanisms affecting brain development and emotional behaviour in the offspring. We also tested the antioxidant N-acetyl-cysteine (NAC) in preventing the long-term effects of HFD consumption during pregnancy. Methods Female C57BL/6N mice were fed HFD before and during pregnancy (13 weeks); after 5 weeks, half of them received NAC (1g/kg) for 8 weeks. Emotionality and social behaviour of male and female adolescent offspring (35-45 days) were assessed through the elevated plus maze (EPM) and the social interaction test (SIT); plasma corticosterone levels were assessed under basal conditions and following an acute stress. Gene expression levels of CD68, Bdnf and Nrf2 were measured in hippocampus as markers of microglial activation, brain plasticity and antioxidant capacity respectively by RealTime PCR. We focused on adolescence, an age of vulnerability for the onset of psychopathology. Results HFD offspring showed reduced exploration in the EPM and sociability in the SIT. These effects were associated to decreased hippocampal Bdnf levels in females while males showed increased CD68 expression and reduced basal corticosterone levels. Prenatal NAC administration prevented social anxiety, restored HPA axis basal activity in males and Bdnf levels in females. These effects may be partly mediated by Nrf2, an important regulator of antioxidant defence, as indicated by its upregulation in the hippocampus of both sexes. Conclusions Prenatal HFD showed detrimental sex-dependent effects on brain, neuroendocrine function and emotional behaviour; these changes were buffered by prenatal NAC suggesting that immune and OS signalling may play an important role in foetal programming of adult diseases. Funding: ERANET-NEURON-JTC-2018 Project EMBE