Perinatal modulation of psychiatric disorders programming: oxytocyn and translational study – PERISTRESS

There is a large individual variability in vulnerability to the development of mental illness. In particular, this vulnerability can be programmed by early environmental factors such as exposure to stress during the perinatal period. Indeed, the perinatal period is a privileged window for the programming of the CNS function. We have shown in rats that prenatal stress programs in the adult’s offspring an increased anxiety- and depressive -like behaviour, symptoms that can be found in many humans’ psychiatric disorders. During the perinatal period, the transmission of the effects of prenatal stress from mother to fetus and then to the newborn, involves maternal factors such as increased levels of anxiety and of plasmatic glucocorticoids associated with a decreased maternal care. Indeed, from our previous work, we observed that blockade of the mother's stress-induced glucocorticoids secretion by adrenalectomy during the gestational period, suppresses the prolonged stress-induced corticosteroid response in the adult offspring. These results suggest that stress-induced increase in maternal glucocorticoids may be a mechanism by which PRS impairs the development of the adult offspring's glucocorticoids response. Concerning maternal behavior as an epigenetic modulator, natural variations in maternal care influence HPA axis stress reactivity in the offspring via long-term changes in tissue-specific genes expression. Studies in vivo and in vitro show that maternal licking and grooming increases glucocorticoids’ receptor expression in the offspring. In PRS animal model, we showed that an early adoption, which increases maternal care, reversed the PRS effects on the HPA axis of adult rats and that stress during gestation induces lasting effects on emotional reactivity of the dam rat. Very recently, we found, in rats, that maternal administration of an oxytocin agonist during lactation increases maternal care of stressed dams. Oxytocin is a neurohypophysial hormone known for its ecbolic activity during labor and its role in lactation. However, the function of oxytocin goes far beyond the peripheral regulation of reproduction, and central effects of oxytocin have been the subjects of extensive investigation since the discovery that peripheral or intrahippocampal injection of oxytocin influences learning and memory processes. Oxytocin has prominent effects on social behavior and anxiety, and has potential clinical applications in psychiatric disorders, such as schizophrenia, post-traumatic stress disorder, addiction, and autism. These hormonal maternal factors are the main actors of the programming by prenatal stress in rats. We now want to evaluate in humans the implication of these actors of perinatal programming through the study of the relationship between psychological and neuroendocrine state of the mother and the central nervous system development (prenatal imaging). In conclusions, the involvement of glucocorticoids as a programming factor as well as mother anxiety and maternal care are well documented in animal models and in a less extend manner in humans. Moreover, few translational works exist on involvement of oxytocin as biomarker of the impact of mother mood state on the psychobiological development of the offspring. In this translational context, we develop local and national collaborations with clinician’s experts on perinatology, Pr. O. Baud (Head of the Neonatal Intensive Care Unit, Robert Debré Children’s Hospital, Paris) and psychiatrists expert, Pr. P Thomas (Head of Psychiatry service, CHR Lille) in order to cover a larger expertise on Perinatal Psychiatry from molecules to behaviour both in pre-clinic and clinic models. Our goal is therefore the identification of biomarkers associated with perinatal vulnerability to mental illness. This will pave the way to early therapeutic intervention.