Insulin-like growth factor I and its binding protein-3 are regulators of lactation and maternal responsiveness

András H Lékó,Árpád Dobolyi,Éva Rebeka Szabó,János Hanics,Alán Alpár,Melinda Cservenák

doi:10.1038/s41598-017-03645-5

András H Lékó, Árpád Dobolyi + Show 4 more

Open Access

https://doi.org/10.1038/s41598-017-03645-5

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Abstract

Adaptation to motherhood includes maternal behaviour and lactation during the postpartum period. The major organizing centres of maternal behaviour and lactation are located in the hypothalamic medial preoptic area (MPOA) and the arcuate nucleus, respectively. Insulin-like growth factor I (IGF-I) is an effector of the growth hormone axis; however, its function in the brain is largely unexplored. We identified increased maternal IGF binding protein-3 (IGFBP-3) expression in preoptic rat microarray data and confirmed it by RT-PCR. In situ hybridization histochemistry showed markedly elevated IGFBP-3 expression in the MPOA and the arcuate nucleus in rat dams. Prolonged intracerebroventricular injection of IGF-I or antagonism of brain IGFBP-3 with an inhibitor (NBI-31772) using osmotic minipumps increased pup retrieval time, suggesting reduced maternal motivation. Suckling-induced prolactin release and pup weight gain were also suppressed by IGF-I, suggesting reduced lactation. In addition, IGF-I-induced tyrosine hydroxylase expression and its specific phosphorylation in tuberoinfundibular dopaminergic neurons suppress prolactin secretion. Thus, IGF-I may inhibit both behavioural and lactational alterations in mothers. Neurons in the MPOA and arcuate nuclei express IGFBP-3 during the postpartum period to neutralize IGF-I effects. IGFBP-3 can prevent the blockade of maternal behaviour and lactation exerted by IGF-I, suggesting a novel modulatory mechanism underlying the behavioural and hormonal effects during central maternal adaptations.

Highlights

Postpartum physiological and behavioural changes are important parts of mammalian reproduction, and they can be investigated using the rat as an animal model
We found a high degree of co-localization; 67.3% of tuberoinfundibular dopaminergic (TIDA) neurons contained insulin-like growth factor binding protein-3 (IGFBP-3) and 85.9% of IGFBP-3 neurons contained Tyrosine hydroxylase (TH) immunoreactivity, suggesting that in the arcuate nucleus of lactating mothers (n = 5), IGFBP-3 mRNA expression is markedly elevated in TH-immunoreactive dopaminergic neurons
There are some differences between the designs of the two studies, including rats vs. mice, postpartum day 9 vs. 7, non-maternal females vs. virgin females as the control group, and dissected tissue from the whole preoptic area vs. only the medial preoptic area

Summary

Introduction

Postpartum physiological and behavioural changes are important parts of mammalian reproduction, and they can be investigated using the rat as an animal model. Non-maternal females do not care about pups or even attack them, while mothers demonstrate well-defined maternal behaviours, e.g., nest building, pup retrieval to the nest, nursing, and decreased anxiety, in addition to lactation. These marked changes are the consequences of maternal adaptation of the central nervous system. IGFBP-3 is normally expressed in the adult central nervous system (CNS) at a low level, mainly in non-neuronal cells, and the effects of IGFBP-3 on the CNS are largely unknown[24,25,26,27,28]. The effects of IGF-I on lactation and prolactin release, an important aspect of reproduction, have not been investigated

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