Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus

doi:10.1016/S0304-3940(01)02544-7

Neuroscience Letters

Volume 321, Issue 3, 22 March 2002, Pages 157-160

https://doi.org/10.1016/S0304-3940(01)02544-7 Get rights and content

Abstract

Ghrelin is a novel peptide that stimulates the release of growth hormone from the pituitary and is involved in hypothalamic feeding regulation. A pre-embedding immunostaining technique was used to study the ultrastructure and synaptic relationships of ghrelin-containing neurons in the rat arcuate nucleus (ARC). Ghrelin-like immunoreactive (ghrelin-LI) neurons were found in the ARC, and were especially abundant in its ventral part. At the electron microscopic level, ghrelin-LI neurons received afferent synapses from many unknown axon terminals. Ghrelin-LI products in the immunoreactive cell bodies, processes, and axon terminals were detected mainly in dense granular vesicles about 110 nm in diameter. Ghrelin-LI presynaptic axon terminals often made synapses with unknown immunonegative neurons. These results suggest that ghrelin acts to regulate food intake through synaptic connections in hypothalamic neuronal networks.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (to J.-L.G. and S.S.) and CREST of JST (to S.S.).

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Olfactory Ensheathing Cells (OECs) are glial cells able to secrete different neurotrophic growth factors and thus promote axonal growth, also acting as a mechanical support. In the olfactory system, during development, they drive the non-myelinated axons of the Olfactory Receptor Neurons (ORNs) towards the Olfactory Bulb (OB). Ghrelin (Ghre), a gut-brain peptide hormone, and its receptor (GHS-R 1a) are expressed in different parts of the central nervous system. In the last few years, this peptide has stimulated particular interest as results show it to be a neuroprotective factor with antioxidant, anti-inflammatory and anti-apoptotic properties.
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Here, we report that the human isoform displays an equivalent neuroprotective factor. However, while exogenous administration of mouse ghrelin electrically activates SN DA neurons increasing dopamine output, as well as locomotion, the human isoform significantly suppressed dopamine output, with an associated decrease in animal motor behavior. Investigating the mechanisms by which GHSR mediates neuroprotection, we found that dopamine cell-selective control of electrical activity is neither sufficient nor necessary to promote SN DA neuron survival, including that associated with GHSR activation. We found that Dln101 pre-treatment diminished MPTP-induced mitochondrial aberrations in SN DA neurons and that the effect of Dln101 to protect dopamine cells was dependent on mitofusin 2, a protein involved in the process of mitochondrial fusion and tethering of the mitochondria to the endoplasmic reticulum.
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Citation Excerpt :
Circulating ghrelin is enhanced following hunger (Cummings et al., 2001; Cummings, Frayo, Marmonier, Aubert, & Chapelot, 2004). Ghrelin containing neurons and ghrelin mRNA is detected in the brain, raising the possibly that ghrelin is produced in parts of the brain (Cowley et al., 2003; Lu et al., 2002; Mondal et al., 2005). Ghrelin has been ascribed numerous feeding-related functions, from an increase in food intake and appetite (Egecioglu et al., 2010; Wren et al., 2001; Wren et al., 2001; Wren et al., 2000) to an initiation of meal (Cummings et al., 2001) as well as an enhanced adiposity (Theander-Carrillo et al., 2006; Tschop, Smiley, & Heiman, 2000).
Due to the limited efficacy of existing medications for addictive disorders including alcohol use disorder (AUD), the need for additional medications is substantial. Potential new medications for addiction can be identified through investigation of the neurochemical substrates mediating the ability of drugs of abuse such as alcohol to activate the mesolimbic dopamine system. Interestingly, recent studies implicate neuropeptides of the gut-brain axis as modulators of reward and addiction processes. The present review therefore summarizes the current studies investigating the ability of the gut-brain peptides ghrelin, glucagon-like peptide-1 (GLP-1), amylin and neuromedin U (NMU) to modulate alcohol- and drug-related behaviors in rodents and humans. Extensive literature demonstrates that ghrelin, the only known orexigenic neuropeptide to date, enhances reward as well as the intake of alcohol, and other drugs of abuse, while ghrelin receptor antagonism has the opposite effects. On the other hand, the anorexigenic peptides GLP-1, amylin and NMU independently inhibits reward from alcohol and drugs of abuse in rodents. Collectively, these rodent and human studies imply that central ghrelin, GLP-1, amylin and NMU signaling may contribute to addiction processes. Therefore, the need for randomized clinical trials investigating the effects of agents targeting these aforementioned systems on drug/alcohol use is substantial.
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Understanding the neurobiological controls of feeding behavior is critical in light of the growing obesity pandemic, a phenomenon largely based on excessive caloric consumption. Feeding behavior and its underlying biological substrates are frequently divided in the literature into two separate categories: [1] homeostatic processes involving energy intake based on caloric and other metabolic deficits, and [2] non-homeostatic processes that involve feeding driven by environmental and cognitive factors. The present review summarizes both historic and recent research examining the homeostatic regulation of feeding with specific emphasis on hypothalamic and hindbrain circuitry that monitor and regulate various metabolic signals. Regarding non-homeostatic controls, we highlight higher-order brain structures that integrate feeding-relevant external, interoceptive, and cognitive factors, including sensory cortical processing, learned associations in the hippocampus, and reward-based processing in the nucleus accumbens and interconnected mesolimbic circuitry. Finally, the current review focuses on recent evidence that challenges the traditional view that distinct neural systems regulate homeostatic vs. non-homeostatic controls of feeding behavior. Specifically, we highlight several feeding-related endocrine systems that act on both lower- and higher-order substrates, present evidence for the modulation of learned and cognitive feeding-relevant behaviors by lower-order brain regions, and highlight data showing that apparent homeostatic-based feeding behavior is modulated by higher-order brain regions. Our concluding perspective is that the classic dissociation between homeostatic and non-homeostatic constructs in relation to feeding behavior is limited with regards to understanding the complex integrated neurobiological systems that control energy balance.
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Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus

Abstract

Section snippets

Acknowledgements

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Brain Res.

Biochem. Biophys. Res. Commun.

Brain Res.

Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus

Neuroendocrinology

Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6

Endocrinology

A receptor subtype involved in neuropeptide-Y-induced food intake

Nature

Amygdala neurons: converging synaptic inputs produced by median eminence and medial preoptic area stimulations in rat

J. Physiol.