The Prolactin Family of Hormones as Regulators of Maternal Mood and Behavior

Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health. Dynamic fluctuations in key hormones during pregnancy and lactation induce these maternal adaptations by acting on neural circuits in the brain. Amongst these hormonal changes, lactogenic hormones (e.g., prolactin and its pregnancy-specific homolog, placental lactogen) are important regulators of these processes, and their receptors are located in key brain regions controlling emotional behaviors and maternal responses. With pregnancy and lactation also being associated with a marked elevation in the risk of developing mood disorders, it is important to understand how hormones are normally regulating mood and behavior during this time. It seems likely that pathological changes in mood could result from aberrant expression of these hormone-induced behavioral responses. Maternal mental health problems during pregnancy and the postpartum period represent a major barrier in developing healthy mother-infant interactions which are crucial for the child's development. In this review, we will examine the role lactogenic hormones play in driving a range of specific maternal behaviors, including motivation, protectiveness, and mother-pup interactions. Understanding how these hormones collectively act in a mother's brain to promote nurturing behaviors toward offspring will ultimately assist in treatment development and contribute to safeguarding a successful pregnancy.

Fenugreek Stimulates the Expression of Genes Involved in Milk Synthesis and Milk Flow through Modulation of Insulin/GH/IGF-1 Axis and Oxytocin Secretion

We previously demonstrated galactagogue effect of fenugreek in a rat model of lactation challenge, foreshadowing its use in women’s breastfeeding management. To assess longitudinal molecular mechanisms involved in milk synthesis/secretion in dams submitted to fenugreek supplementation, inguinal mammary, pituitary glands and plasma were isolated in forty-three rats nursing large 12 pups-litters and assigned to either a control (CTL) or a fenugreek-supplemented (FEN) diet during lactation. RT-PCR were performed at days 12 and 18 of lactation (L12 and L18) and the first day of involution (Inv1) to measure the relative expression of genes related to both milk synthesis and its regulation in the mammary gland and lactogenic hormones in the pituitary gland. Plasma hormone concentrations were measured by ELISA. FEN diet induced 2- to 3-times higher fold change in relative expression of several genes related to macronutrient synthesis (Fasn, Acaca, Fabp3, B4galt1, Lalba and Csn2) and energy metabolism (Cpt1a, Acads) and in IGF-1 receptor in mammary gland, mainly at L12. Pituitary oxytocin expression and plasma insulin concentration (+77.1%) were also significantly increased. Altogether, these findings suggest fenugreek might extend duration of peak milk synthesis through modulation of the insulin/GH/IGF-1 axis and increase milk ejection by activation of oxytocin secretion.

SUN-LB45 Identifying a Role for Lactogenic Hormones in Maternal Motivation

The onset of appropriate maternal behaviour is essential for the survival of dependent offspring in mammals. Lactogenic hormones, including prolactin and placental lactogen, play an important role in the regulation of this behaviour, mediated through prolactin receptor expression in the medial preoptic area (MPOA) of the hypothalamus1. However, it is unclear how lactogenic action in this region induces the display of maternal behaviour. It has been shown that activation of neuronal projections from the MPOA to the ventral tegmental area (VTA) is necessary for maternal behaviour2, with reward circuitry activated in order to motivate a mother to invest in time- and resource-costly care for her young. We aimed to investigate whether lactogenic hormones play a role in the activation of reward circuitry for maternal behaviour. First, we characterised specific aspects of motivation and reward behaviour in wildtype female C57BL/6 mice of different reproductive states, using three behavioural testing paradigms. We showed that virgin and pregnant mice develop a preference for contexts associated with the presence of foster pups in a conditioned place preference test (p<0.01, n=9 per group), an aspect of reward behaviour that was not observed in lactating females (p=0.14, n=8). However, in a novel T maze and when a climbable barrier was placed in the home cage, virgin and pregnant mice showed low motivation for pup retrieval compared to lactating mice (p<0.05, n≤6 per group). These data demonstrate that reproductive state differentially affects passive reward learning and active motivation for maternal care in wildtype mice. Moreover, we can differentiate between maternal and non-maternal states of pup-related reward behaviour with the use of the T maze and barrier climbing paradigms. Next, we tested mice with a conditional deletion of prolactin receptors in Gamma-Aminobutyric Acid (GABA) neurons (Prlr flox/VGat Cre) in the T maze during lactation. Knockout mice showed incomplete retrieval behaviour, and latencies for pup retrieval were significantly longer than in controls (p<0.01, n≤6 per group). The behavioural impairments observed in Prlr flox/VGat Cre knockout mice in the T maze imply that the action of lactogenic hormones on GABA neurons is required for full maternal motivation. 1.Brown RSE, et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc Natl Acad Sci U S A114, 10779-10784 (2017). 2.Fang YY, Yamaguchi T, Song SC, Tritsch NX, Lin D. A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors. Neuron98, 192-207 e110 (2018).

Lactogenic hormones regulate mammary protein synthesis in bovine mammary epithelial cells via the mTOR and JAK–STAT signal pathways

The expression of CSN3, hormone receptor, the expression of genes regulating the mTOR, JAK–STAT signal pathways, and the relative content of к-casein as well as total casein were determined in the present study to explore the mechanism of the effect of lactogenic hormones on milk-protein synthesis in bovine mammary epithelial cells. The results showed that apoptosis of the cells was increased by inhibitor LY294002, while the expressions of genes encoding PKB, Rheb, PRAS40 and S6K1 in the mTOR signal pathway, JAK2, STAT5A in the JAK–STAT signal pathway, and genes encoding INSR, PRLR, NR3C1 and CSN3 were all downregulated, and the relative contents of κ-casein and total casein were decreased in the mammary epithelial cells compared with those in the control group. Comparatively, the inhibitory effects of AG-490 were more profound than those of LY294002, and the double block using both inhibitors had a greater effect than the single block. The CSN3 gene expression was downregulated and the content of milk casein was decreased by the inhibitors. In addition, the expression of the hormone receptor genes was downregulated. Our results suggest that lactogenic hormones, via their receptors in the membrane, regulated the JAK–STAT and m-TOR signal pathways, and affected cell proliferation and apoptosis, leading to changes in milk-protein synthesis.