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Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

ABSTRACT: The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesis and release. Because neurokinin B (NKB) increases in the hypothalamus as puberty approaches, we considered it a candidate for such a role. An initial study investigated the acute effects of an NKB agonist, senktide, on the secretion of DYN from MBH tissues incubated in vitro. In other experiments, central injections of senktide were administered to animals for 4 days then MBHs were collected for assessment of DYN synthesis or for the in vitro secretion of both DYN and GnRH. Because insulin-like growth factor (IGF)-1 has been shown to play an important role at puberty, additional animals received central injections of this peptide for 4 days to assess NKB and DYN synthesis or the in vitro secretion of NKB. The results obtained show that senktide administration up-regulates the NKB receptor protein, at the same time as suppressing the DYN and its receptor. Senktide consistently suppressed DYN and elevated GnRH secretion in the same tissue incubates from both the acute and chronic studies. IGF-1 administration caused an increase in NKB protein, at the same time as decreasing DYN protein. Furthermore, the central administration of IGF-1 caused an increase in NKB release, an action blocked by the IGF-1 receptor blocker, JB-1. These results indicate that the IGF-1/NKB pathway contributes to suppressing the DYN inhibitory tone on prepubertal GnRH secretion and thus facilitates the puberty-related increase in the release of GnRH to accelerate the onset of puberty.

SUBMITTER: Dees WL

PROVIDER: S-EPMC6916394 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

Dees William L WL Hiney Jill K JK Srivastava Vinod K VK

Journal of neuroendocrinology 20191201 12

The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesi ...[more]

PMID: 31715027

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Project description:BackgroundKisspeptins bind to the G-protein-coupled receptor (GPR54) to activate hypothalamic luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. Alcohol (ALC) causes depressed prepubertal LHRH release, resulting in depressed luteinizing hormone (LH) secretion and delayed puberty. Because KiSS-1 and GPR54 are important to the onset of puberty, we assessed the effects of chronic ALC administration on basal expression of these puberty-related genes within the reproductive hypothalamus, as well as hormones and transduction signaling pathways contributing to their activity.MethodsImmature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Controls received either companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Blood was collected for the assessment of serum hormone levels. Brain tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were obtained for assessing expression of specific puberty-related genes and proteins.ResultsKiSS-1 mRNA levels in the AVPV and ARC nuclei were suppressed (p < 0.001) in the ALC-treated rats. GPR54 gene and protein expressions were both modestly increased (p < 0.05) in AVPV nucleus, but not in ARC nucleus. Alcohol exposure also resulted in suppressed serum levels of insulin-like growth factor-1 (IGF-1), LH, and estradiol (E(2)). As IGF-1, in the presence of E(2), can induce expression of the KiSS-1 gene, we assessed the potential for ALC to alter IGF-1 signaling in the reproductive hypothalamus. IGF-1 receptor gene and protein expressions were not altered. However, protein expression of phosphorylated Akt, a transduction signal used by IGF-1, was suppressed in the AVPV (p < 0.05) and ARC (p < 0.01) nuclei.ConclusionsAlcohol causes suppressed KiSS-1 gene expression in the reproductive hypothalamus; hence, contributing to this drug's ability to cause suppressed LHRH secretion and disruption of the pubertal process. We suggest that this action, at least in part, is through altered IGF-1 signaling.

Project description:Glial-derived transforming growth factor alpha (TGFα) activates the erbB1/erbB2 receptor complex on adjacent glial cells in the medial basal hypothalamus (MBH). This receptor activation stimulates the synthesis and release of prostaglandin-E(2) (PGE(2)) from the glial cells, which then induces the release of prepubertal luteinizing hormone-releasing hormone (LHRH) secretion from nearby nerve terminals; thus, showing the importance of glial-neuronal communications at the time of puberty. Ethanol (EtOH) is known to cause depressed prepubertal LHRH secretion and delayed pubertal development. In this study, we assessed whether short-term EtOH exposure could alter the hypothalamic glial to glial signaling components involved in prepubertal PGE(2) secretion. Immature female rats began receiving control or EtOH diets beginning when 27 days old. The animals were killed by decapitation after 4 and 6 days of treatment and confirmed to be in the late juvenile stage of development. Blood and brain tissues were collected for gene, protein, and hormonal assessments. Real-time polymerase chain reaction (PCR) analysis demonstrated that EtOH did not affect basal levels of erbB1 gene expression in the MBH. Expression of total erbB1 protein was also unaffected; however, the EtOH caused suppressed phosphorylation of erbB1 protein in the MBH at both 4 and 6 days (P<.01) as revealed by Western blotting. Phosphorylation and total protein levels of erbB2 receptor were not affected by EtOH exposure. Because this receptor is critical for PGE(2) synthesis/release, which mediates the secretion of LHRH, we assessed whether in vivo EtOH exposure could affect the release of PGE(2). EtOH exposure for 6 days suppressed (P<.01) basal levels of PGE(2) released into the medium. The effects of 4- and 6-day EtOH exposure on gene and protein expressions of TGFα, an upstream component in the activation of erbB1/erbB2, were also studied. The levels of TGFα mRNA were increased markedly at 4 days (P<.001), but declined to near basal levels by 6 days in the EtOH-treated animals. The EtOH caused increases in TGFα protein expression at both 4 (P<.001) and 6 (P<.01) days; hence, suggesting that the EtOH inhibited release of the peptide. We confirmed this inhibition by showing decreased (P<.01) TGFα released from MBHs incubated in vitro following 6 days of EtOH exposure in vivo. Thus, these results demonstrate that EtOH is capable of interfering with hypothalamic glial to glial signaling processes involved in prepubertal PGE(2) secretion.

Dataset Information

Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

Publications

Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

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