Understanding Postpartum Mood Disorders: Characterization of Brain Nuclei Activated by Prolactin Induced Signalling

Abstract

It has previously been hypothesized that the state of prolonged hyperprolactinemia (elevated lactogenic hormones prolactin, placental lactogen I or placental lactogen II) during pregnancy signals to the brain to organize and coordinate all of the adaptations of pregnancy, including the reduction of anxiety and onset of normal maternal behavior postpartum. When this reduction in responsiveness to stress does not occur to the extent that it should, this can result in pathological postpartum anxiety. The aim of this study was to characterize serum prolactin levels during pregnancy and early lactation in mice, and additionally to determine when and where in the brain these lactogenic hormones act during this time. Immunohistochemistry for pSTAT5 was used to examine lactogenic induced activation of nuclei in the brain. Radioimmunoassay was used to evaluate serum prolactin levels in virgin mice in diestrus, on days 3, 7, 11, 17 and 19 of pregnancy, and on postpartum day 2. An additional group of mice were injected with progesterone twice daily from day 17 to day 18 of pregnancy and once on day 19 to prevent the pre-parturition drop in progesterone, and surge in prolactin. Serum prolactin levels were significantly elevated on day 3 of pregnancy during a crest, on day 19 of pregnancy and on postpartum day 2. Prolactin levels were significantly decreased on day 19 of pregnancy in mice injected with progesterone compared to day 19 control mice. In the LS, BnST, RP3V, MPOA, PVN, ARC and VMN lactogenic induced signaling was significantly elevated in early pregnancy, compared to virgin controls. In these same regions in mid pregnancy and early lactation, there was a trend for an increase in lactogenic induced signaling, but the increase was not statistically significant. These results suggest that placental lactogens act through the JAK2/pSTAT5 pathway during pregnancy but not to the same extent as prolactin in early pregnancy. This may be due to chronically high levels of placental lactogens stimulating ligand induced receptor desensitization. Progesterone injections in late pregnancy prevented the pre-parturition surge in prolactin and resulted in an increase in lactogenic-induced signalling in the RP3V, MPOA and VMN. Thus, the pre-parturition drop in progesterone may be a requirement for the pre-parturition surge in prolactin. Furthermore, elevated progesterone levels may have a stimulatory effect on lactogenic induced signaling within the brain. These data demonstrate that the heightened sensitivity to prolactin that is seen postpartum in the maternal brain, which is correlated with normal expression of maternal behaviors, occurs by day 3 of pregnancy. These results contribute to the understanding of the mechanisms underlying the maternal adaptations necessary for maternal and fetal wellbeing, and thus, offer insight into new directions for future research identifying therapeutic treatments for impairments in maternal behaviors.