CORT induced hippocampal damage has been implicated in depre

CORT-induced hippocampal damage has been implicated in depression, aging and long-term glucocorticoid therapy. Therefore, finding a drug that can protect hippocampal neurons from the adverse effects of CORT could have significant clinical benefits. In this regard, we tested the potential protective role of OT in CORT-induced apoptosis, as OT is released in response to stressful stimuli and has been shown to have antidepressant- and antianxiety-like effects in animal studies (Arletti and Bertolini, 1987, Matsushita et al., 2010). In our study, OT counteracted the action of CORT and protects the hippocampal neurons from apoptosis. To confirm whether anti-apoptotic effects of OT were mediated via OTR, we tested the effect of CORT and OT using primary hippocampal cultures derived from OTR KO mice. As OT failed to rescue hippocampal neurons from CORT-induced apoptosis in the absence of OTR, it was concluded that OT acts via OTR to protect them. There are some limitations in interpretation of our results. Firstly, we used in vitro cultures of hippocampal neurons to test our hypothesis. They are different in a number of ways from mature neurons in the adult brain. They do not have a structural and humoral support of a network of glial cells. They do not have extensive connections with other functionally distinct neurons as in the adult brain. Their transcriptome might be different from adult neurons. Secondly, CORT levels that can amount to significant cytotoxicity to hippocampal neurons in our study are relatively high compared to levels that can be achieved in a stress paradigm in vivo. Peak plasma CORT levels in mice that can be achieved by acute or chronic stress were reported around 1000 ng/mL (i.e., 2.9 μM) (Gong et al., 2015). It seems that mouse hippocampal neurons in primary cultures were resistant to CORT, and we reasoned that high resistance of hippocampal neurons to CORT might be partly related to difference in expression of GR either in terms of the number or the isotype, as well as in glucocorticoid metabolism. Varga et al. (2013) reported that in the hypothalamus, hippocampus, and prefrontal transketolase in rat pups, the expression and protein levels of GR and mineralocorticoid receptors were decreased compared to adult animals, while those of 11beta-hydroxysteroid dehydrogenase 2, an enzyme which converts CORT and cortisol into inactive metabolites, were increased. Whether this is also true in mice should be answered with future experiments. Although our results cannot be directly interpreted into what would be observed in vivo, our findings highlighted the possible mechanism of OT acting as an antagonist against a stress hormone, CORT, in young and developing hippocampal neurons. As primary hippocampal neurons are retrieved from newborn mice, they can be viewed as young, and immature neurons developing to form a mature neuronal network in the face of challenges such as the process of labor, adaptation to external world, and in our case, artificial environment. This time in life coincides with stress non-responsive period during which the HPA axis is less responsive to stressful stimuli (Schapiro, 1968). Although the underlying mechanisms were not very clear, this might reduce the exposure of developing neurons from the toxic effects of glucocorticoids. The process of labor also results in a dramatic increase in plasma OT level in mother, which might cause a parallel increase of plasma OT in fetuses. In humans, fetal plasma OT levels were significantly higher after vaginal delivery than after elective cesarean section (Kuwabara et al., 1987, Marchini et al., 1988). OT in fetal plasma also seems to come from the fetal pituitary, as evidenced by significantly higher plasma levels in the umbilical artery compared to maternal levels (de Geest et al., 1985). Current and previous findings suggest the role of OT as a neuroprotective agent in the developing brain. Previous studies have linked perturbed OT signaling to several neurodevelopmental and psychiatric disorders, and many tried to evaluate its potential application in such patients. Intranasal OT has been shown to have positive effects in patients with post-traumatic stress disorder (Olff et al., 2015, Frijling et al., 2016; van Zuiden et al., 2016) and major depressive disorder (Scantamburlo et al., 2015, Domes et al., 2016). Despite these developments in appraising OT as a therapeutic agent in stress-related disorders, the therapeutic value of OT in the context of psychotherapy remains limited, and needs both basic science and translational research for further evaluation.