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Lance J Kriegsfeld - One of the best experts on this subject based on the ideXlab platform.
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Time-of-day-dependent sensitivity of the reproductive axis to RFamide-Related Peptide-3 inhibition in female Syrian hamsters.
Journal of neuroendocrinology, 2019Co-Authors: Neta Gotlieb, Cydni N. Baker, Jacob Moeller, Lance J KriegsfeldAbstract:In spontaneously ovulating rodent species, the timing of the luteinising hormone (LH) surge is controlled by the master circadian pacemaker in the suprachiasmatic nucleus (SCN). The SCN initiates the LH surge via the coordinated control of two opposing neuroPeptidergic systems that lie upstream of the gonadotrophin-releasing hormone (GnRH) neuronal system: the stimulatory Peptide, kisspeptin, and the inhibitory Peptide, RFamide-Related Peptide-3 (RFRP-3; the mammalian orthologue of avian gonadotrophin-inhibitory hormone [GnIH]). We have previously shown that the GnRH system exhibits time-dependent sensitivity to kisspeptin stimulation, further contributing to the precise timing of the LH surge. To examine whether this time-dependent sensitivity of the GnRH system is unique to kisspeptin or a more common mechanism of regulatory control, we explored daily changes in the response of the GnRH system to RFRP-3 inhibition. Female Syrian hamsters were ovariectomised to eliminate oestradiol (E2 )-negative-feedback and RFRP-3 or saline was centrally administered in the morning or late afternoon. LH concentrations and Lhβ mRNA expression did not differ between morning RFRP-3-and saline-treated groups, although they were markedly suppressed by RFRP-3 administration in the afternoon. However, RFRP-3 inhibition of circulating LH at the time of the surge does not appear to act via the GnRH system because no differences in medial preoptic area Gnrh or RFRP-3 receptor Gpr147 mRNA expression were observed. Rather, RFRP-3 suppressed arcuate nucleus Kiss1 mRNA expression and potentially impacted pituitary gonadotrophs directly. Taken together, these findings reveal time-dependent responsiveness of the reproductive axis to RFRP-3 inhibition, possibly via variation in the sensitivity of arcuate nucleus kisspeptin neurones to this neuroPeptide.
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Gonadotrophin-inhibitory hormone and its mammalian orthologue RFamide-Related Peptide-3: Discovery and functional implications for reproduction and stress
Journal of neuroendocrinology, 2018Co-Authors: Lance J Kriegsfeld, George E. Bentley, Kimberly J. Jennings, Kazuyoshi TsutsuiAbstract:At the turn of the millennium, a neuroPeptide with pronounced inhibitory actions on avian pituitary gonadotrophin secretion was identified and named gonadotrophin-inhibitory hormone (GnIH). Across bird species, GnIH acts at the level of the pituitary and the gonadotrophin-releasing hormone (GnRH) neuronal system to inhibit reproduction. Subsequent to this initial discovery, orthologues of GnIH have been identified and characterised across a broad range of species. In many vertebrates, the actions of GnIH and its orthologues serve functional roles analogous to those seen in birds. In other cases, GnIH and its orthologues exhibit more diverse actions dependent on sex, species, season and reproductive condition. The present review highlights the discovery and functional implications of GnIH across species, focusing on research domains in which the significance of this neuroPeptide has been explored most.
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RFamide-Related Peptide-3 and the Trade-off between Reproductive and Ingestive Behavior.
Integrative and comparative biology, 2017Co-Authors: Jill E. Schneider, Wilbur P. Williams, Noah A. Benton, Kim A. Russo, Candice M. Klingerman, Jessica Simberlund, Amir Abdulhay, Jeremy M. Brozek, Lance J KriegsfeldAbstract:Ingestive and sex behaviors are important for individual survival and reproductive success, but when environmental energy availability is limited, individuals of many different species make a trade-off, forfeiting sex for ingestive behavior. For example, food-deprived female Syrian hamsters (Mesocricetus auratus) forego vaginal scent marking and lordosis (sex behaviors) in favor of foraging, hoarding, and eating food (ingestive behavior). Reproductive processes tend to be energetically costly, and individual survival requires homeostasis in metabolic energy. Thus, during energetic challenges, the chances of survival are enhanced by decreasing the energy expended on reproductive processes. The entire hypothalamic-pituitary-gonadal (HPG) system is inhibited by severe energetic challenges, but comparatively little is known about the effects of mild energetic challenges. We hypothesized that (1) a trade-off is made between sex and ingestive behavior even when the level of food restriction is insufficient to inhibit the HPG system; (2) mild energetic challenges force a trade-off between appetitive ingestive and sex behaviors, but not consummatory versions of the same behaviors; and (3) the trade-off is orchestrated by ovarian steroid modulation of RFamide-Related Peptide 3 (RFRP-3). In other species, RFRP-3, an ortholog of avian gonadotropin-inhibitory hormone, is implicated in control of behavior in response to energetic challenges and stressful stimuli. In support of our three hypotheses, there is a "dose-response" effect of food restriction and re-feeding on the activation of RFRP-3-immunoreactive cells in the dorsomedial hypothalamus and on appetitive behaviors (food hoarding and sexual motivation), but not on consummatory behaviors (food intake and lordosis), with no significant effect on circulating levels of estradiol or progesterone. The effect of food restriction on the activation of RFRP-3 cells is modulated at the time of estrus in gonadally-intact females and in ovariectomized females treated with progesterone alone or with estradiol plus progesterone. Intracerebral treatment with RFRP-3 results in significant decreases in sexual motivation and results in significant but small increases in food hoarding in hamsters fed ad libitum. These and other results are consistent with the idea that ovarian steroids and RFRP-3 are part of a system that orchestrates trade-offs in appetitive behaviors in environments where energy availability fluctuates.
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Food restriction-induced changes in motivation differ with stages of the estrous cycle and are closely linked to RFamide-Related Peptide-3 but not kisspeptin in Syrian hamsters
Physiology & behavior, 2017Co-Authors: Noah A. Benton, Lance J Kriegsfeld, Kim A. Russo, Jeremy M. Brozek, Ryan J. Andrews, Veronica J. Kim, Jill E. SchneiderAbstract:We tested the hypothesis that the effects of food restriction on behavioral motivation are mediated by one or both of the RFamide Peptides, RFamide-Related Peptide-3 (RFRP-3) and kisspeptin (Kp) in female Syrian hamsters (Mesocricetus auratus). Female hamsters fed ad libitum and given a choice between food and adult male hamsters are highly motivated to visit males instead of food on all four days of the estrous cycle, but after 8days of mild food restriction (75% of ad libitum intake) they shift their preference toward food every day of the estrous cycle until the day of estrus, when they shift their preference back toward the males. In support of a role for RFRP-3 in these behavioral changes, the preference for food and the activation of RFRP-3-immunoreactive (Ir) cells in the dorsomedial hypothalamus (DMH) showed the same estrous cycle pattern in food-restricted females, but no association was observed between behavior and the activation of Kp cells in the hypothalamic arcuate nucleus or preoptic area. Next, we tested the hypothesis that food-restriction-induced activation of RFRP-3-Ir cells is modulated by high levels of ovarian steroids at the time of estrus. In support of this idea, on nonestrous days, mild food restriction increased activation of RFRP-3-Ir cells, but failed to do so on the day of estrus even though this level of food restriction did not significantly decrease circulating concentrations of estradiol or progesterone. Furthermore, in ovariectomized females, food-restriction-induced increases in activation of RFRP-3-Ir cells were blocked by systemic treatment with progesterone alone, estradiol plus progesterone, but not estradiol alone. Central infusion with RFRP-3 in ad libitum-fed females significantly decreased sexual motivation and produced significant increases in 90-minute food hoarding, in support of the hypothesis that elevated central levels of RFRP-3 are sufficient to create the shift in behavioral motivation in females fed ad libitum. Together, these results are consistent with the hypothesis that high levels of ingestive motivation are promoted during the nonfertile phase of the estrous cycle by elevated activation of RFRP-3-Ir cells, and RFRP-3-Ir cellular activation is modulated by ovarian steroids around the time of estrus, thereby diverting attention away from food and increasing sexual motivation.
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The preoptic area and the RFamide-Related Peptide neuronal system gate seasonal changes in chemosensory processing
Integrative and Comparative Biology, 2017Co-Authors: Kimberly J. Jennings, Hweyryoung Cho, Manon Chasles, Jens Mikkelsen, George Bentley, Matthieu Keller, Lance J KriegsfeldAbstract:Males of many species rely on chemosensory information for social communication. In male Syrian hamsters (Mesocricetus auratus), as in many species, female chemosignals potently stimulate sexual behavior and a concurrent, rapid increase in circulating luteinizing hormone (LH) and testosterone (T). However, under winter-like, short-day (SD) photoperiods, when Syrian hamsters are reproductively quiescent, these same female chemosignals fail to elicit behavioral or hormonal responses, even after T replacement. It is currently unknown where in the brain chemosensory processing is gated in a seasonally dependent manner such that reproductive responses are only displayed during the appropriate breeding season. The goal of the present study was to determine where this gating occurred by identifying neural loci that respond differentially to female chemosignals across photoperiods, independent of circulating T concentrations. Adult male Syrian hamsters were housed under either long-day (LD) (reproductively active) or SD (reproductively inactive) photoperiods with half of the SD animals receiving T replacement. Animals were exposed to either female hamster vaginal secretions (FHVSs) diluted in mineral oil or to vehicle, and the activational state of chemosensory processing centers and elements of the neuroendocrine reproductive axis were examined. Components of the chemosensory pathway upstream of hypothalamic centers increased expression of FOS, an indirect marker of neuronal activation, similarly across photoperiods. In contrast, the preoptic area (POA) of the hypothalamus responded to FHVS only in LD animals, consistent with its role in promoting expression of male sexual behavior. Within the neuroendocrine axis, the RF-amide related Peptide (RFRP), but not the kisspeptin neuronal system responded to FHVS only in LD animals. Neither response within the POA or the RFRP neuronal system was rescued by T replacement in SD animals, mirroring photoperiodic regulation of reproductive responses. Considering the POA and the RFRP neuronal system promote reproductive behavior and function in male Syrian hamsters, differential activation of these systems represents a potential means by which photoperiod limits expression of reproduction to the appropriate environmental context.
Kazuyoshi Tsutsui - One of the best experts on this subject based on the ideXlab platform.
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Role of RFRP-3 in the Regulation of Kiss-1 Gene Expression in the AVPV Hypothalamic Cell Model mHypoA-50
Reproductive Sciences, 2019Co-Authors: Haruhiko Kanasaki, Kazuyoshi Tsutsui, Tuvshintugs Tumurbaatar, Aki Oride, Tomomi Hara, Hiroe Okada, Zolzaya Tumurgan, Satoru KyoAbstract:Kisspeptin, encoded by the Kiss-1 gene, plays a crucial role in reproductive function by governing the hypothalamic—pituitary—gonadal axis. The recently established Kiss-1-expressing cell model mHypoA-50 displays characteristics of neuronal cells of the anteroventral periventricular (AVPV) region of the mouse hypothalamus. Because Kiss-1 gene expression in these cells is upregulated by estradiol (E2), mHypoA-50 cells are regarded as a valuable model for the study of Kiss-1-expressing neurons in the AVPV region. These cells also express RFamide-Related Peptide-3 (RFRP-3), a mammalian homolog of gonadotropin inhibitory hormone. The RFRP-3 expression in mHypoA-50 cells was increased by melatonin stimulation. In addition, E2 stimulation increased RFRP-3 expression in these cells. Treatment of the mHypoA-50 cells with exogenous RFRP-3 resulted in the increase of Kiss-1 messenger RNA expression within the cells; however, RFRP-3 did not modify gonadotropin-releasing hormone or kisspeptin-induced Kiss-1 gene expression in these cells. In addition, we found that RFRP-3 stimulation increased the expression of corticotropin-releasing hormone, which may be involved in E2-induced positive feedback in mHypoA-50 cells. Our observations suggest that RFRP-3 might be involved in positive feedback regulation by directly or indirectly increasing Kiss-1 gene expression.
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action of neurotensin corticotropin releasing hormone and rfamide related Peptide 3 in e2 induced negative feedback control studies using a mouse arcuate nucleus hypothalamic cell model
Biology of Reproduction, 2018Co-Authors: Tuvshintugs Tumurbaatar, Kazuyoshi Tsutsui, Haruhiko Kanasaki, Aki Oride, Tomomi Hara, Hiroe Okada, Satoru KyoAbstract:The recently established immortalized hypothalamic cell model mHypoA-55 possesses characteristics similar to those of Kiss-1 neurons in the arcuate nucleus (ARC) region of the hypothalamus. Here, we show that Kiss-1 gene expression in these cells was downregulated by 17β-estradiol (E2) under certain conditions. Both neurotensin (NT) and corticotropin-releasing hormone (CRH) were expressed in these cells and upregulated by E2. Stimulation of mHypoA-55 cells with NT and CRH significantly decreased Kiss-1 mRNA expression. A mammalian gonadotropin-inhibitory hormone homolog, RFamide-Related Peptide-3 (RFRP-3), was also found to be expressed in mHypoA-55 cells, and RFRP-3 expression in these cells was increased by exogenous melatonin stimulation. E2 stimulation also upregulated RFRP-3 expression in these cells. Stimulation of mHypoA-55 cells with RFRP-3 significantly increased the expression of NT and CRH. Furthermore, melatonin stimulation resulted in the increase of both NT and CRH mRNA expression in mHypoA-55 cells. On the other hand, in experiments using mHypoA-50 cells, which were originally derived from hypothalamic neurons in the anteroventral periventricular nucleus, Kiss-1 gene expression was upregulated by both NT and CRH, although E2 increased both NT and CRH expression, similarly to the mHypoA-55 cells. Our observations using the hypothalamic ARC cell model mHypoA-55 suggest that NT and CRH have inhibitory effects on Kiss-1 gene expression under the influence of E2 in association with RFRP-3 expression. Thus, these neuroPeptides might be involved in E2-induced negative feedback mechanisms.
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Gonadotrophin-inhibitory hormone and its mammalian orthologue RFamide-Related Peptide-3: Discovery and functional implications for reproduction and stress
Journal of neuroendocrinology, 2018Co-Authors: Lance J Kriegsfeld, George E. Bentley, Kimberly J. Jennings, Kazuyoshi TsutsuiAbstract:At the turn of the millennium, a neuroPeptide with pronounced inhibitory actions on avian pituitary gonadotrophin secretion was identified and named gonadotrophin-inhibitory hormone (GnIH). Across bird species, GnIH acts at the level of the pituitary and the gonadotrophin-releasing hormone (GnRH) neuronal system to inhibit reproduction. Subsequent to this initial discovery, orthologues of GnIH have been identified and characterised across a broad range of species. In many vertebrates, the actions of GnIH and its orthologues serve functional roles analogous to those seen in birds. In other cases, GnIH and its orthologues exhibit more diverse actions dependent on sex, species, season and reproductive condition. The present review highlights the discovery and functional implications of GnIH across species, focusing on research domains in which the significance of this neuroPeptide has been explored most.
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The roles of RFamide-Related Peptides (RFRPs), mammalian gonadotropin-inhibitory hormone (GnIH) orthologues in female reproduction
Iranian journal of basic medical sciences, 2018Co-Authors: Huimei Wang, Kazuyoshi Tsutsui, Mohammad Salehi, Mohammad Reza Jafarzadeh Shirazi, Arezoo Khoradmehr, Mohammad Jalali, Amin TamadonAbstract:Objective(s): To benefit from reproduction and deal with challenges in the environmental conditions, animals must adapt internal physiology to maximize the reproduction rate. Maladaptive variations in the neurochemical systems and reproductive system can lead to manifestation of several significant mammalian reprocesses, including mammalian ovarian lifespan. RFamide-Related Peptide (RFRP, Rfrp), mammalian orthologues of gonadotropin-inhibitory hormone (GnIH), which is a regulator to prevent the gonadotropin-releasing hormone (GnRH) neural activity, is known to be related to reproductive traits. This review aimed to summarize recent five-year observations to outline historic insights and novel perspectives into the functions of RFRPs in coding the mammalian reproductive physiology, especially highlight recent advances in the impact on RFRPs in regulating mammalian ovary lifespan.Materials and Methods: We reviewed the recent five-year important findings of RFRP system involved in mammalian ovary development. Data for this review were collected from Google Scholar and PubMed using the RFRP keyword combined with the keywords related to physiological or pathological reproductive functions.Results: Recent discoveries are focused on three major fronts in research on RFRP role in female reproduction including reproductive functions, energy balance, and stress regulation. The roles of RFRPs in various development phases of mammal reproduction including prepuberty, puberty, estrous cycle, pregnancy, milking, menopause, and/or ovarian diseases have been shown.Conclusion: Overall, these recent advances demonstrate that RFRPs serve as critical mediators in mammalian ovarian development.
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Differential expression of RFamide-Related Peptide, a mammalian gonadotrophin-inhibitory hormone orthologue, and kisspeptin in the hypothalamus of Abadeh ecotype does during breeding and anoestrous seasons
Journal of neuroendocrinology, 2014Co-Authors: M. R. Jafarzadeh Shirazi, Kazuyoshi Tsutsui, Mohammad Salehi, Mohammad Javad Zamiri, Mohammad Reza Namavar, Amin Tamadon, Sara Moradi, Amir Akhlaghi, Alain CaratyAbstract:Gonadotrophin-inhibitory hormone (GnIH) is a novel hypothalamic neuroPeptide that was discovered in birds as an inhibitory factor for gonadotrophin release. RFamide-Related Peptide (RFRP) is a mammalian GnIH orthologue that inhibits gonadotrophin synthesis and release in mammals through actions on gonadotrophin-releasing hormone (GnRH) neurones and gonadotrophs, mediated via the GnIH receptor (GnIH-R), GPR147. On the other hand, hypothalamic kisspeptin provokes the release of GnRH from the hypothalamus. The present study aimed to compare the expression of RFRP in the dorsomedial hypothalamus and paraventricular nucleus (DMH/PVN) and that of kisspeptin in the arcuate nucleus (ARC) of the female goat hypothalamus during anoestrous and breeding seasons. Mature female Abadeh does were used during anoestrus, as well as the follicular and luteal phases of the cycle. The number of RFRP-immunoreactive (-IR) neurones in the follicular phase was lower than in the luteal and anoestrous stages. Irrespective of the ovarian stage, the number of RFRP-IR neurones in the rostral and middle regions of the DMH/PVN was higher than in the caudal region. By contrast, the number of kisspeptin-IR neurones in the follicular stage was greater than in the luteal stage and during the anoestrous stage. Irrespective of the stage of the ovarian cycle, the number of kisspeptin-IR neurones in the caudal region of the ARC was greater than in the middle and rostral regions. In conclusion, RFRP-IR cells were more abundant in the rostral region of the DMH/PVN nuclei of the hypothalamus, with a greater number being found during the luteal and anoestrous stages compared to the follicular stage. On the other hand, kisspeptin-IR neurones were more abundant in the caudal part of the ARC, with a greater number recorded in the follicular stage compared to the luteal and anoestrous stages.
Greg M. Anderson - One of the best experts on this subject based on the ideXlab platform.
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RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Asha Mamgain, Mohammed Z. Rizwan, Megan A Inglis, India L. Sawyer, David A.m. Timajo, Maggie C. Evans, Caroline Ancel, Greg M. AndersonAbstract:RF-amide related Peptide 3 (RFRP-3) is a neuroPeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.
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Anti-opioid Effects of RFRP-3 on Magnocellular Neuron Activity in Morphine-naïve and Morphine-treated Female Rats.
Endocrinology, 2016Co-Authors: Joon S. Kim, Colin H. Brown, Greg M. AndersonAbstract:NeuroPeptide FF receptors (NPFFR1 and NPFFR2) have been proposed to possess anti-opioid properties, and be involved in the development of opiate tolerance and dependence. However, there is no evidence to date supporting such opioid effects at the cellular level in vivo. Using in vivo electrophysiological recordings from vasopressin and oxytocin neurons in the supraoptic nucleus, we aimed to determine the effects of NPFFRs on opiate inhibition, tolerance, and dependence at a cellular level. Both vasopressin and oxytocin neurons are acutely inhibited by opioids and develop opiate tolerance. Oxytocin neurons also develop cellular opiate dependence and undergo withdrawal hyperexcitation upon cessation of opiate administration. Here, the classical μ-opioid receptor agonist, morphine robustly inhibited the spontaneous firing rate of vasopressin and oxytocin neurons, and this inhibition was attenuated by pretreatment with the NPFFR1 agonist, RFamide-Related Peptide-3. In rats infused with morphine for 6 d, vasop...
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No Evidence That RFamide-Related Peptide 3 Directly Modulates LH Secretion in the Ewe.
Endocrinology, 2016Co-Authors: Caroline Decourt, Greg M. Anderson, Karine Anger, Vincent Robert, Didier Lomet, Julien Bartzen-sprauer, Alain Caraty, Laurence Dufourny, Massimiliano BeltramoAbstract:The neuroPeptide RFamide-Related Peptide 3 (RFRP-3) has been implicated in the control of gonadotropin secretion in both birds and mammals. However, in mammals, depending on species, sex and photoperiod, inhibitory, excitatory, or no effect of RFRP-3 on the plasma concentration of LH has been reported. In the ewe, treatment with RFRP-3 either reduced LH concentration or had no effect, and treatment with an RFRP-3 receptor antagonist (ie, RF9) resulted in increased concentration of plasma LH. To clarify these conflicting results in the present study, a set of experiments was performed in ewes. Multiple iv injections of RFRP-3 (6 × 50 μg) in ovariectomized ewes had no effect on plasma LH pulsatility. In intact ewes a bolus injection (500 μg) or an injection (250, 500, or 1000 μg) followed by a 4-hour perfusion (250, 500, or 1000 μg · h(-1)) of RFRP-3 had no effect on the LH pulse induced by kisspeptin (6.5 μg). In ovariectomized, estrogen-replaced ewes, the LH surge induced by estradiol benzoate was not modified by a 24-hour perfusion of RFRP-3 (500 μg h(-1)). Finally, although treatment with RF9 induced a robust release of LH, treatment with a more selective RFRP-3 receptor antagonist, GJ14, resulted in no evident increase of LH. In contrast to the inhibitory effect previously suggested, our data are more consistent with the concept that RFRP-3 has no direct effect on LH secretion in ewes and that RF9 effect on LH release is likely not RFRP-3 receptor mediated. Hence, RFRP-3 probably has a minor role on the control of LH secretion in the ewe.
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Anxiogenic and stressor effects of the hypothalamic neuroPeptide RFRP-3 are overcome by the NPFFR antagonist GJ14
Endocrinology, 2015Co-Authors: Joon S. Kim, Massimiliano Beltramo, Phil W. Brownjohn, Blake S. Dyer, Christopher S. Walker, Debbie L. Hay, Gavin F. Painter, Joel D.a. Tyndall, Greg M. AndersonAbstract:RFamide-Related Peptide-3 (RFRP-3) is a recently discovered neuroPeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, NPFF1R, in modulation of stress and anxiety responses. To achieve this, we developed a new NPFF1R antagonist, since our results showed that the only commercially available putative antagonist, RF9 is in fact an agonist at both NPFF1R and the kisspeptin receptor, KISS1R. We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in corticotropin-releasing hormone (CRH) neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior while RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, co-infusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here, we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.
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evidence that hypothalamic rfamide related Peptide 3 neurones are not leptin responsive in mice and rats
Journal of Neuroendocrinology, 2014Co-Authors: Mohammed Z. Rizwan, Janette H. Quennell, Anan A. Harbid, Megan A Inglis, Greg M. AndersonAbstract:Leptin, a permissive hormonal regulator of fertility, provides information about the body's energy reserves to the hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal system that drives reproduction. Leptin does not directly act on GnRH neurones, and the neuronal pathways that it uses remain unclear. RFamide-Related Peptide-3 (RFRP-3) neurones project to GnRH neurones and primarily inhibit their activity. We tested whether leptin could act via RFRP-3 neurones to potentially modulate GnRH activity. First, the effects of leptin deficiency or high-fat diet-induced obesity on RFRP-3 cell numbers and gene expression were assessed in male and female mice. There was no significant difference in Rfrp mRNA levels or RFRP-3-immunoreactive cell counts in wild-type versus leptin-deficient ob/ob animals, or in low-fat versus high-fat diet fed wild-type mice. Second, the presence of leptin-induced signalling in RFRP-3 neurones was examined in male and female wild-type mice and rats. Dual label immunohistochemistry revealed leptin-induced phosphorylated signal transducer and activator of transcription-3 in close proximity to RFRP-3 neurones, although there was very little (2-13%) colocalisation and no significant differences between vehicle and leptin-treated animals. Furthermore, we were unable to detect leptin receptor mRNA in a semi-purified RFRP-3 cell preparation. Because GABA neurones form critical leptin-responsive GnRH inputs, we also determined whether RFRP-3 and GABA cells were colocalised. No such colocalisation was detected. These results support the concept that leptin has little or no effects on RFRP-3 neurones, and that these neurones are unlikely to be an important neuronal pathway for the metabolic regulation of fertility by leptin.
George E. Bentley - One of the best experts on this subject based on the ideXlab platform.
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Gonadotrophin-inhibitory hormone and its mammalian orthologue RFamide-Related Peptide-3: Discovery and functional implications for reproduction and stress
Journal of neuroendocrinology, 2018Co-Authors: Lance J Kriegsfeld, George E. Bentley, Kimberly J. Jennings, Kazuyoshi TsutsuiAbstract:At the turn of the millennium, a neuroPeptide with pronounced inhibitory actions on avian pituitary gonadotrophin secretion was identified and named gonadotrophin-inhibitory hormone (GnIH). Across bird species, GnIH acts at the level of the pituitary and the gonadotrophin-releasing hormone (GnRH) neuronal system to inhibit reproduction. Subsequent to this initial discovery, orthologues of GnIH have been identified and characterised across a broad range of species. In many vertebrates, the actions of GnIH and its orthologues serve functional roles analogous to those seen in birds. In other cases, GnIH and its orthologues exhibit more diverse actions dependent on sex, species, season and reproductive condition. The present review highlights the discovery and functional implications of GnIH across species, focusing on research domains in which the significance of this neuroPeptide has been explored most.
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RFamide-Related Peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal.
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Diana E. Peragine, George E. Bentley, Martha Pokarowski, Lucia Mendoza-viveros, Ashlyn Swift-gallant, Hai-ying M. Cheng, Melissa M. HolmesAbstract:Abstract Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-Related Peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory Peptides are the ultimate gatekeepers of puberty.
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The Role of RFamide-Related Peptide-3 in Age-Related Reproductive Decline in Female Rats.
Frontiers in endocrinology, 2016Co-Authors: Anna C Geraghty, Lance J Kriegsfeld, George E. Bentley, Sandra E Muroy, Daniela KauferAbstract:Reproductive senescence, the point in time when females cease to show estrous cyclicity, is associated with endocrine changes in the hypothalamus, pituitary, and gonads. However, the mechanisms triggering this transition are not well understood. To gain a better understanding of the top-down control of the transition from reproductive competence to a state of reproductive senescence, we investigated middle-aged female rats exhibiting varying degrees of reproductive decline, including individuals with normal cycles, irregular cycles, and complete cessation of cycles. We identified hormonal changes in the brain that manifest before ovarian cycles exhibit any deterioration. We found that females exhibit an increase in RFamide-Related Peptide-3 (RFRP3) mRNA expression in the hypothalamus in middle age prior to changes in estrous cycle length. This increase is transient and followed by subsequent decreases in kisspeptin (KiSS1) and gonadotropin-releasing hormone (GnRH) mRNA expression. Expression of RFRP3 and its receptor also increased locally in the ovaries with advancing age. While it is well known that aging is associated with decreased GnRH release and downstream disruption of the hypothalamic-pituitary-gonadal (HPG) axis, herein, we provide evidence that reproductive senescence is likely triggered by alterations in a network of regulatory neuroPeptides upstream of the GnRH system.
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Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption
eLife, 2015Co-Authors: Anna C Geraghty, Lance J Kriegsfeld, Sheng Zhao, George E. Bentley, Sandra E Muroy, Daniela KauferAbstract:Whereas it is well established that chronic stress induces female reproductive dysfunction, whether stress negatively impacts fertility and fecundity when applied prior to mating and pregnancy has not been explored. In this study, we show that stress that concludes 4 days prior to mating results in persistent and marked reproductive dysfunction, with fewer successful copulation events, fewer pregnancies in those that successfully mated, and increased embryo resorption. Chronic stress exposure led to elevated expression of the hypothalamic inhibitory Peptide, RFamide-Related Peptide-3 (RFRP3), in regularly cycling females. Remarkably, genetic silencing of RFRP3 during stress using an inducible-targeted shRNA completely alleviates stress-induced infertility in female rats, resulting in mating and pregnancy success rates indistinguishable from non-stress controls. We show that chronic stress has long-term effects on pregnancy success, even post-stressor, that are mediated by RFRP3. This points to RFRP3 as a potential clinically relevant single target for stress-induced infertility.
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The human gonadotropin-inhibitory hormone ortholog RFamide-Related Peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells
Endocrinology, 2012Co-Authors: Hajime Oishi, Kazuyoshi Tsutsui, George E. Bentley, Christian Klausen, Tomohiro Osugi, C. Blake Gilks, Tetsu Yano, Peter C.k. LeungAbstract:RFamide-Related Peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone, has pronounced inhibitory effects on reproduction in a number of species. RFRP-3 suppresses gonadotropin release at the hypothalamic and/or pituitary levels; however, increasing evidence also suggests putative functions within the ovary. We have now demonstrated the expression of both RFRP and its receptor (GPR147) in primary cultures of human granulosa-lutein cells. Immunohistochemical analysis of normal human ovaries from premenopausal women showed that RFRPs and GPR147 were primarily localized in the granulosa cell layer of large preovulatory follicles as well as in the corpus luteum. Treatment of human granulosa-lutein cells with RFRP-3 reduced FSH-, LH- and forskolin-stimulated progesterone production and steroidogenic acute regulatory protein expression but did not affect basal or 8-bromoadenosine 3′5′-cyclic monophosphate stimulated levels. In addition, RFRP-3 inhibited gonadotropin- and forskolin-ind...
Tatsushi Onaka - One of the best experts on this subject based on the ideXlab platform.
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effects of rfamide related Peptide rfrp 1 and rfrp 3 on oxytocin release and anxiety related behaviour in rats
Journal of Neuroendocrinology, 2011Co-Authors: Maroot Kaewwongse, Yuki Takayanagi, Tatsushi OnakaAbstract:RFamide-Related Peptides (RFRP-1 and RFRP-3) are localised in neurones of the dorsomedial hypothalamus in rats. The dorsomedial hypothalamus plays an essential role in neuroendocrine and behavioural stress responses. In the present study, we examined the role of RFRP in the control of neuroendocrine and behavioural responses in rats. Stressful stimuli increased expression of Fos protein in RFRP-immunoreactive neurones of the dorsomedial hypothalamus, suggesting that stressful stimuli activate RFRP neurones. Intracerebroventricular injection of RFRPs increased the expression of Fos protein in oxytocin neurones in the hypothalamus and plasma concentrations of adrenocorticotrophic hormone and oxytocin. The hypothalamic paraventricular and supraoptic nuclei expressed mRNA of GPR147, the putative RFRP receptor, and application of RFRPs to isolated supraoptic nuclei facilitated oxytocin release, suggesting that RFRPs activate oxytocin neurones directly. Furthermore, the administration of RFRPs induced anxiety-related behaviour in rats in open-field tests. All these data taken together suggest that RFRPs play a role in the control of neuroendocrine and behavioural stress responses in rats.
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Effects of RFamide‐Related Peptide (RFRP)‐1 and RFRP‐3 on Oxytocin Release and Anxiety‐Related Behaviour in Rats
Journal of Neuroendocrinology, 2010Co-Authors: Maroot Kaewwongse, Yuki Takayanagi, Tatsushi OnakaAbstract:RFamide-Related Peptides (RFRP-1 and RFRP-3) are localised in neurones of the dorsomedial hypothalamus in rats. The dorsomedial hypothalamus plays an essential role in neuroendocrine and behavioural stress responses. In the present study, we examined the role of RFRP in the control of neuroendocrine and behavioural responses in rats. Stressful stimuli increased expression of Fos protein in RFRP-immunoreactive neurones of the dorsomedial hypothalamus, suggesting that stressful stimuli activate RFRP neurones. Intracerebroventricular injection of RFRPs increased the expression of Fos protein in oxytocin neurones in the hypothalamus and plasma concentrations of adrenocorticotrophic hormone and oxytocin. The hypothalamic paraventricular and supraoptic nuclei expressed mRNA of GPR147, the putative RFRP receptor, and application of RFRPs to isolated supraoptic nuclei facilitated oxytocin release, suggesting that RFRPs activate oxytocin neurones directly. Furthermore, the administration of RFRPs induced anxiety-related behaviour in rats in open-field tests. All these data taken together suggest that RFRPs play a role in the control of neuroendocrine and behavioural stress responses in rats.
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Roles of prolactin‐releasing Peptide and RFamide related Peptides in the control of stress and food intake
The FEBS journal, 2010Co-Authors: Yuki Takayanagi, Tatsushi OnakaAbstract:Subsequent to the isolation of the first recognized RFamide neuroPeptide, FMRFamide, from the clam, a large number of these Peptides have been identified. There are now five groups of RFamide Peptides identified in mammals. RFamide Peptides show diversity with respect to their N-terminal sequence and biological activity. RFamide Peptides have been implicated in a variety of roles, including energy metabolism, stress and pain modulation, as well as effects in the neuroendocrine and cardiovascular systems. In the present minireview, we focus on prolactin-releasing Peptide (PrRP) and RFamide related Peptide (RFRP) with respect to their roles in the control of energy metabolism and stress responses. Both food intake and stressful stimuli activate PrRP neurons. The administration of PrRP affects energy metabolism and neuroendocrine systems. PrRP-deficient or PrRP receptor-deficient mice show abnormal energy metabolism and/or stress responses. On the other hand, RFRP neurons are activated by stressful stimuli and the administration of RFRP induces neuroendocrine and behavioral stress responses. Taken together, these data suggests that PrRP and RFRP neurons play a role in the control of energy metabolism and/or stress responses.