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Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus.

Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F, Fehrentz JA, Carmignac D, Martinez J, Guerineau NC, Robinson IC, Mollard P, Méry PF - PLoS ONE (2010)

Bottom Line: 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.These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.

View Article: PubMed Central - PubMed

Affiliation: Inserm U-661, Montpellier, France.

ABSTRACT

Background: 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.

Principal findings: 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.

Conclusion: 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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Related in: MedlinePlus

Ghrelin enhances the firing rates of GHRH neurons in the absence of somatostatin.A, typical experiment where 10 nM ghrelin increased the firing rate of a GHRH neuron from an adult male somatostatin −/−, GHRH-GFP mouse (raw traces are shown on the top). B, summary of the effects of ghrelin (10 nM) on the distributions of action potential frequencies in GHRH neurons from adult male somatostatin −/−, GHRH-GFP mice. Symbols and lines are the means and the sem of the numbers of experiments indicated. Statistical significances (p<0.05, paired student-t test, see methods) between curves are framed by the grey area.
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pone-0009159-g005: Ghrelin enhances the firing rates of GHRH neurons in the absence of somatostatin.A, typical experiment where 10 nM ghrelin increased the firing rate of a GHRH neuron from an adult male somatostatin −/−, GHRH-GFP mouse (raw traces are shown on the top). B, summary of the effects of ghrelin (10 nM) on the distributions of action potential frequencies in GHRH neurons from adult male somatostatin −/−, GHRH-GFP mice. Symbols and lines are the means and the sem of the numbers of experiments indicated. Statistical significances (p<0.05, paired student-t test, see methods) between curves are framed by the grey area.

Mentions: Both GHRH neurons and somatostatinergic neurons express some GHSR [10]. The effect of ghrelin on the GH axis might require synaptic signalling between these two neuronal populations [1]. Accordingly, we took the opportunity to examine the effect of ghrelin on GHRH neurons in the absence of somatostatin, by breeding GHRH-GFP mice onto a somatostatin knockout mouse background [47] (a description of GHRH neurons of these animals is the subject of another submission). Fig. 5A shows that an identified GHRH neuron in an adult male somatostatin knockout mouse exhibited a spontaneous firing rate of ∼0.9 Hz under control conditions, increasing to ∼3.3 Hz upon addition of 10 nM ghrelin to the external solution. This stimulation was found in each experiment performed in GHRH neurons from GHRH-GFP X somatostatin mice, and their mean spontaneous activity was significantly enhanced, as summarized in Fig. 5B (p<0.05 in the 0.5–6.5 Hz range, paired student's t-test where). A lower concentration of ghrelin (1 nM) had no significant effect (n = 3, data not shown). Thus, the activation of hypothalamic GHRH neurons by ghrelin occurs in the absence of somatostatin.


Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus.

Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F, Fehrentz JA, Carmignac D, Martinez J, Guerineau NC, Robinson IC, Mollard P, Méry PF - PLoS ONE (2010)

Ghrelin enhances the firing rates of GHRH neurons in the absence of somatostatin.A, typical experiment where 10 nM ghrelin increased the firing rate of a GHRH neuron from an adult male somatostatin −/−, GHRH-GFP mouse (raw traces are shown on the top). B, summary of the effects of ghrelin (10 nM) on the distributions of action potential frequencies in GHRH neurons from adult male somatostatin −/−, GHRH-GFP mice. Symbols and lines are the means and the sem of the numbers of experiments indicated. Statistical significances (p<0.05, paired student-t test, see methods) between curves are framed by the grey area.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2820089&req=5

pone-0009159-g005: Ghrelin enhances the firing rates of GHRH neurons in the absence of somatostatin.A, typical experiment where 10 nM ghrelin increased the firing rate of a GHRH neuron from an adult male somatostatin −/−, GHRH-GFP mouse (raw traces are shown on the top). B, summary of the effects of ghrelin (10 nM) on the distributions of action potential frequencies in GHRH neurons from adult male somatostatin −/−, GHRH-GFP mice. Symbols and lines are the means and the sem of the numbers of experiments indicated. Statistical significances (p<0.05, paired student-t test, see methods) between curves are framed by the grey area.
Mentions: Both GHRH neurons and somatostatinergic neurons express some GHSR [10]. The effect of ghrelin on the GH axis might require synaptic signalling between these two neuronal populations [1]. Accordingly, we took the opportunity to examine the effect of ghrelin on GHRH neurons in the absence of somatostatin, by breeding GHRH-GFP mice onto a somatostatin knockout mouse background [47] (a description of GHRH neurons of these animals is the subject of another submission). Fig. 5A shows that an identified GHRH neuron in an adult male somatostatin knockout mouse exhibited a spontaneous firing rate of ∼0.9 Hz under control conditions, increasing to ∼3.3 Hz upon addition of 10 nM ghrelin to the external solution. This stimulation was found in each experiment performed in GHRH neurons from GHRH-GFP X somatostatin mice, and their mean spontaneous activity was significantly enhanced, as summarized in Fig. 5B (p<0.05 in the 0.5–6.5 Hz range, paired student's t-test where). A lower concentration of ghrelin (1 nM) had no significant effect (n = 3, data not shown). Thus, the activation of hypothalamic GHRH neurons by ghrelin occurs in the absence of somatostatin.

Bottom Line: 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.These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.

View Article: PubMed Central - PubMed

Affiliation: Inserm U-661, Montpellier, France.

ABSTRACT

Background: 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.

Principal findings: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus