Upregulation of PVN CRHR1 by gestational intermittent hypoxia selectively triggers a male-specific anxiogenic effect in rat offspring.

We previously reported that gestational intermittent hypoxia (GIH) causes anxiety-like behavior in neonatal rats. Here, we showed that the anxiogenic effect was correlated with upregulation of corticotropin-releasing hormone receptor 1 (CRHR1) in the hypothalamic paraventricular nuclei (PVN) by GIH, and was selective to male offspring. The anxiety-like behavior was assessed by both the open field (OF) and elevated plus maze (EPM) tests. We demonstrated that GIH triggered anxiety-like behavior in male offspring, but not in female offspring or in the postpartum dams. Microinjection of antalarmin, a CRHR1-selective antagonist, into the PVN of the male offspring significantly increased the distance traveled and time spent in the central portion of the OF, and the time spent in the open arms in the EPM compared with controls. However, microinjection of the CRHR2 agonist, urocortin III, into the PVN did not affect anxiogenic behavior in the male offspring. These findings clearly demonstrate a gender-selective effect of GIH to increase anxiety-like behavior and this anxiogenic effect might be linked to embryogenically-driven upregulation of PVN CRHR1.