Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

Inserm U-661, Montpellier, France.
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e9159. DOI: 10.1371/journal.pone.0009159
Source: PubMed


Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin.
Here, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by gamma-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate.
Thus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.

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    • "This is further supported by the fact that, in these experimental models, ghrelin-mediated [Ca 2+ ]i rises are sensitive to N-type (Kohno et al., 2008) or L-type (Grey & Chang, 2009) Ca 2+ channel blockade, respectively. Moreover, Ca 2+ channel opening is required for observing excitatory effects of ghrelin on hypothalamic GHRH neurons (Osterstock et al., 2010). By contrast, blocking IP3 receptors with xestospongin-C does not seem to alter ghrelin-mediated CREB activation in CA1 hippocampal neurons (Cuellar & Isokawa, 2011). "
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    ABSTRACT: Acute effects of ghrelin on excitatory synaptic transmission were evaluated on hippocampal CA1 synapses. Ghrelin triggered an enduring enhancement of synaptic transmission independently of NMDA receptor activation and likely via postsynaptic modifications. This ghrelin-mediated potentiation resulted from the activation of GHS-R1a receptors as it was mimicked by the selective agonist JMV1843 and blocked by the selective antagonist JMV2959. This potentiation also required the activation of PKA and ERK pathways to occur since it was inhibited by KT5720 and U0126, respectively. Moreover it most likely involved Ca2+ influxes as both ghrelin and JMV1843 elicited intracellular Ca2+ increases, which were dependent on the presence of extracellular Ca2+ and mediated by L-type Ca2+ channels opening. In addition, ghrelin potentiated AMPA receptor-mediated [Ca2+]i increases while decreasing NMDA receptor-mediated ones. Thus the potentiation of synaptic transmission by GHS-R1a at hippocampal CA1 excitatory synapses likely results from postsynaptic mechanisms involving PKA and ERK activation, which are producing long-lasting enhancement of AMPA receptor-mediated responses. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Neuroscience 07/2015; DOI:10.1111/ejn.13013 · 3.18 Impact Factor
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    • "Although several studies have shown that intra-amygdala injection of ghrelin enhances memory retention on a passive avoidance task [16], [19], [20], [21], so far there is no study demonstrating the possible effect of ghrelin on CTA memory formation. In addition, ghrelin was previously shown to directly increase the firing rate of NPY/AgRP neurons, GHRH neurons in the arcuate nucleus and dopaminergic neurons in the substantia nigra pars compacta as well [22], [23], [24], however its effect on neuronal excitability in lateral amygdala and the behavioral relevance has not been reported yet. Therefore, the aim of the present study is to explore the acute effects of ghrelin on neuronal activity within the LA and extend these findings to behavioral outputs of amygdala: CTA memory acquisition and expression. "
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    ABSTRACT: Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. An increasing number of studies have reported that ghrelin and its identified receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), produces remarkably wide and complex functions and biological effects on specific populations of neurons in central nervous system. In this study, we sought to explore the in vivo effects of acute ghrelin exposure on lateral amygdala (LA) neurons at the physiological and behavioral levels. In vivo extracellular single-unit recordings showed that ghrelin with the concentration of several nanomolars (nM) stimulated spontaneous firing of the LA neurons, an effect that was dose-dependent and could be blocked by co-application of a GHS-R1a antagonist D-Lys3-GHRP-6. We also found that D-Lys3-GHRP-6 inhibited spontaneous firing of the LA neurons in a dose-dependent manner, revealing that tonic GHS-R1a activity contributes to orchestrate the basal activity of the LA neurons. Behaviorally, we found that microinfusion of ghrelin (12 ng) into LA before training interfered with the acquisition of conditioned taste aversion (CTA) as tested at 24 h after conditioning. Pre-treatment with either purified IgG against GHS-R1a or GHS-R1a antagonist blocked ghrelin's effect on CTA memory acquisition. Ghrelin (12 ng) had no effect on CTA memory consolidation or the expression of acquired CTA memory; neither did it affect the total liquid consumption of tested rats. Altogether, our data indicated that ghrelin locally infused into LA blocks acquisition of CTA and its modulation effects on neuronal firing may be involved in this process.
    PLoS ONE 06/2013; 8(6):e65422. DOI:10.1371/journal.pone.0065422 · 3.23 Impact Factor
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    • "Consequently, we used GT1-7 cells to explore how this pathway is involved in hypothalamic ghrelin signalling. Previous work has indicated that ghrelin directly depolarizes and increases the firing rate of hypothalamic arcuate neurons, including NPY-containing neurons [5, 38]. Ghrelin also raises [Ca2+]i levels in neurons and glia [39, 40, 41]. "
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    ABSTRACT: Activation of mammalian target of rapamycin 1 (mTORC1) by nutrients, insulin and leptin leads to appetite suppression (anorexia). Contrastingly, increased AMP-activated protein kinase (AMPK) activity by ghrelin promotes appetite (orexia). However, the interplay between these mechanisms remains poorly defined. The relationship between the anorexigenic hormones, insulin and leptin, and the orexigenic hormone, ghrelin, on mTORC1 signalling was examined using S6 kinase phosphorylation as a marker for changes in mTORC1 activity in mouse hypothalamic GT1-7 cells. Additionally, the contribution of AMPK and mTORC1 signalling in relation to insulin-, leptin- and ghrelin-driven alterations to mouse hypothalamic agouti-related protein (AgRP) mRNA levels was examined. Insulin and leptin increase mTORC1 activity in a phosphoinositide-3-kinase (PI3K)- and protein kinase B (PKB)-dependent manner, compared to vehicle controls, whereas increasing AMPK activity inhibits mTORC1 activity and blocks the actions of the anorexigenic hormones. Ghrelin mediates an AMPK-dependent decrease in mTORC1 activity and increases hypothalamic AgRP mRNA levels, the latter effect being prevented by insulin in an mTORC1-dependent manner. In conclusion, mTORC1 acts as an integration node in hypothalamic neurons for hormone-derived PI3K and AMPK signalling and mediates at least part of the assimilated output of anorexigenic and orexigenic hormone actions in the hypothalamus.
    Neurosignals 03/2012; 21(1-2). DOI:10.1159/000334144 · 2.00 Impact Factor
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