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      The maternal hormone in the male brain: Sexually dimorphic distribution of prolactin signalling in the mouse brain

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          Abstract

          Research of the central actions of prolactin is highly focused on females, but this hormone has also documented roles in male physiology and behaviour. Here, we provide the first description of the pattern of prolactin-derived signalling in the male mouse brain, employing the immunostaining of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) after exogenous prolactin administration. Next, we explore possible sexually dimorphic differences by comparing pSTAT5 immunoreactivity in prolactin-supplemented males and females. We also assess the role of testosterone in the regulation of central prolactin signalling in males by comparing intact with castrated prolactin-supplemented males. Prolactin-supplemented males displayed a widespread pattern of pSTAT5 immunoreactivity, restricted to brain centres showing expression of the prolactin receptor. Immunoreactivity for pSTAT5 was present in several nuclei of the preoptic, anterior and tuberal hypothalamus, as well as in the septofimbrial nucleus or posterodorsal medial amygdala of the telencephalon. Conversely, non-supplemented control males were virtually devoid of pSTAT5-immunoreactivity, suggesting that central prolactin actions in males are limited to situations concurrent with substantial hypophyseal prolactin release (e.g. stress or mating). Furthermore, comparison of prolactin-supplemented males and females revealed a significant, female-biased sexual dimorphism, supporting the view that prolactin has a preeminent role in female physiology and behaviour. Finally, in males, castration significantly reduced pSTAT5 immunoreactivity in some structures, including the paraventricular and ventromedial hypothalamic nuclei and the septofimbrial region, thus indicating a region-specific regulatory role of testosterone over central prolactin signalling.

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          Social reward requires coordinated activity of accumbens oxytocin and 5HT

          Social behaviors in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviors, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin (OT) acts as a social reinforcement signal within the nucleus accumbens (NAc) core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the NAc receives OT receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-HT) innervation to the NAc, abolishes the reinforcing properties of social interaction. Furthermore, OT-induced synaptic plasticity requires activation of NAc 5-HT1b receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of OT and 5-HT in the NAc, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.
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            Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.

            PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)
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              CD38 is critical for social behaviour by regulating oxytocin secretion.

              CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 December 2018
                2018
                : 13
                : 12
                : e0208960
                Affiliations
                [1 ] Unitat Predepartamental de Medicina, Facultat de Ciències de la Salut, Universitat Jaume I, Castelló de la Plana, Spain
                [2 ] Departament de Biologia Cel·lular i de Biologia Funcional, Facultat de Ciències Biològiques, Universitat de València, València, Spain
                Kent State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9498-7966
                http://orcid.org/0000-0003-3181-4579
                Article
                PONE-D-18-28558
                10.1371/journal.pone.0208960
                6301622
                30571750
                c95b0bd7-dba4-4b26-9a47-215cfea5d209
                © 2018 Salais-López et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 October 2018
                : 27 November 2018
                Page count
                Figures: 4, Tables: 0, Pages: 21
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100010198, Ministerio de Economía, Industria y Competitividad, Gobierno de España;
                Award ID: BFU2016-77691-C2-1-P
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100010198, Ministerio de Economía, Industria y Competitividad, Gobierno de España;
                Award ID: BFU2016-77691-C2-1-P
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100010198, Ministerio de Economía, Industria y Competitividad, Gobierno de España;
                Award ID: BFU2016-77691-C2-2-P
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003359, Generalitat Valenciana;
                Award ID: PROMETEO/2016/076
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004834, Universitat Jaume I;
                Award ID: UJI-B2016-45
                Award Recipient :
                Funded by: Ministerio de Educación, Cultura y Deporte (ES)
                Award ID: FPU12/05472
                Award Recipient :
                F.M.-G. and E.L. were funded by the Spanish Ministry of Economy and Competitiveness-FEDER (BFU2016-77691-C2-2-P and C2-1-P). F.M.-G., C.A.-P. and E.L. were funded by the Generalitat Valenciana (PROMETEO/2016/076). F.M.-G. was funded by the Universitat Jaume I de Castelló (UJI-B2016-45). H.S.-L. has been a predoctoral fellow of the FPU (Formación de Profesorado Universitario) programme of the Spanish Ministry of Education, Culture and Sport (FPU12/05472). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Hormones
                Androgens
                Testosterone
                Biology and Life Sciences
                Biochemistry
                Hormones
                Lipid Hormones
                Testosterone
                Biology and Life Sciences
                Anatomy
                Brain
                Hypothalamus
                Arcuate Nucleus
                Medicine and Health Sciences
                Anatomy
                Brain
                Hypothalamus
                Arcuate Nucleus
                Biology and Life Sciences
                Biochemistry
                Hormones
                Peptide Hormones
                Prolactin
                Biology and Life Sciences
                Developmental Biology
                Morphogenesis
                Sexual Differentiation
                Sexual Dimorphism
                Biology and Life Sciences
                Anatomy
                Brain
                Hypothalamus
                Medicine and Health Sciences
                Anatomy
                Brain
                Hypothalamus
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                STAT signaling
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
                Biology and Life Sciences
                Biochemistry
                Hormones
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                All relevant data are within the manuscript and its Supporting Information files.

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