Early stress may induce alteration of the intrauterine environment, and trigger an epigenetic programming leading to low resilience to stress in the adult life. The model of prenatal restraint stress (PRS) in rodents recapitulates the hallmark of anxious/depressive disorders and schizophrenia. PRS rodents, i.e. the offspring of dams exposed to repeated episodes of stress during pregnancy, show long-term neurochemical and behavioral alterations that likely reflect epigenetic changes in hippocampus and prefrontal cortex, two brain regions that are critically involved in the regulation of emotional behavior.

To elucidate a compelling epigenetic hypothesis, we examined whether PRS in rats may induce transgenerational programming by a single generation of stress, i.e. by mating first-generation (F1) PRS female rats with naïve male rats. In males, most of the features of PRS phenotype persisted in the second-generation (F2), though F2 rats were not directly exposed to stress in utero. Notably, both F1 and F2 rats exhibited anxiety-like behavior, prolonged corticosterone response to stress, and increased brain-derived neurotrophic factor (BDNF) and reduced metabotropic glutamate 2/3 receptor expression in the hippocampus. These changes were associated with a similar deregulation of gene expression in both generations, as well as with a hypomethylation of the BDNF promoter and a hypermethylation of the mineralocorticoid receptor. Also, we investigated variations in maternal care, a behavior that lies at the core of the epigenetic imprinting occurring in early life. Dams exposed to stress during pregnancy (F0, grandmothers) showed a tremendous reduction in the duration of nursing and licking/grooming behavior, combined with anxiety-like behavior during and after the lactation period. Dissimilarly, maternal behavior was only mildly affected in F1 PRS dams that did not display anxiety-like phenotype.

Our results show that the pathological programming induced by PRS can be transmitted across generations independently of maternal behavior.