Expression of c-Fos protein in the brain after intravenous injection of ghrelin in rats

Takayama, Kiyoshige; Johno, Yukimi; Hayashi, Kaori; Yakabi, Koji; Tanaka, Teruyuki; Ro, Shoki

doi:10.1016/j.neulet.2007.02.089

Cited by 40 publications

(50 citation statements)

References 23 publications

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“…This indicates that while AP neurons are in free contact with circulating hormones such as ghrelin, other adjacent caudal brain stem areas, such as the NTS and dorsal motor nucleus are functionally isolated from the circulation. Activation of neurons in the NTS and other brain stem sites by peripheral ghrelin (24,56) is likely to be secondary to modulation of AP neurons (38). Together with the present results, these data suggest that AP is the primary sensor of ghrelin in the caudal brain stem.…”

Section: Examples Of Results From Nonresponding Neurons (A) Hyperpolsupporting

confidence: 75%

“…While the c-Fos immunolabeling technique can provide information regarding increases in neuronal activity, decreases in activity brought about by membrane hyperpolarization cannot be identified. Indeed, some c-Fos immunolabeling studies have reported that ghrelin does not induce c-Fos in the AP (34) or induces only weak immunolabeling (56) and suggested that AP is not an important site of action within the CNS. The fact that 19% of the neurons modulated by ghrelin in this study were hyperpolarized suggests that previous studies have underestimated the ability of AP to detect circulating ghrelin and communicate this information to other sites involved in regulation of energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Injection of ghrelin into the NTS or nearby areas stimulated feeding at doses below the threshold required for forebrain injections (17). Many investigators observe that peripheral administration of ghrelin also caused increases in caudal brain stem c-Fos immunoreactivity (24,37,38,56), although such changes have not been reported in all studies (34). Moreover, recent observations by Gilg and Lutz (21) have convincingly demonstrated a role for AP in ghrelin-mediated feeding.…”

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confidence: 99%

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Ghrelin modulates electrical activity of area postrema neurons

Fry¹,

Ferguson²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ghrelin, a peptide hormone secreted from the stomach, is known to have a potent appetite-stimulating activity. Recently, it has been shown that area postrema (AP), a caudal brain stem center that lacks a blood-brain barrier, is a key site of activity for ghrelin in stimulating appetite and regulating pancreatic protein secretion. In this study, we have examined the ability of ghrelin to regulate the electrical activity of area postrema neurons using patch-clamp electrophysiology. Using current-clamp configuration, we found that at a concentration of 10 nM, ghrelin caused inhibition in 19% of neurons tested, while a further 19% were excited by similar application of ghrelin. The remaining 62% of AP neurons were insensitive to ghrelin. These effects were concentration dependent, with an apparent EC 50 of 1.9 nM. Voltage-clamp recordings revealed that ghrelin caused a potentiation of voltage-gated K ϩ currents in neurons that exhibited a hyperpolarization and a potentiation of a depolarizing nonspecific cation current (NSCC) in those neurons that exhibited a depolarization of membrane potential. These are the first data showing that ghrelin exerts a direct effect on electrical activity of AP neurons and supports the notion that ghrelin can act via the AP to regulate energy homeostasis. patch clamp; action potential; sensory circumventricular organ; energy homeostasis GHRELIN IS AN ACYLATED 28-amino acid peptide hormone, which was discovered on the basis of its activity as an endogenous ligand for the growth hormone secretagogue receptor (GHSR) (35). Originally isolated from the stomach, ghrelin has also been shown to be expressed in various tissues, including the duodenum, adrenal gland, lung, and gonads (22), as well as in neurons in the hypothalamus (11). In addition to its role in the stimulation of growth hormone release in the pituitary, ghrelin is thought to play several roles in the regulation of energy balance. Circulating levels of ghrelin are increased in the fasting state and in anticipation of food (2, 12, 13). Conversely, ghrelin levels are attenuated by feeding and the presence of nutrients in the stomach (58), or by treatment with leptin (2). Administration of ghrelin potently stimulates food intake in rats (58, 64, 65), mice (2), and humans (63). These studies suggest a physiological role in initiation of feeding. Ghrelin is also suggested to play a role in long-term regulation of energy balance, as chronic administration of ghrelin causes weight gain by reducing fat utilization as an energy source (58). Lastly, ghrelin also plays a role in the digestion of food and the stimulation of gastric motility, acid secretion, and pancreatic protein secretion (38, 41).There is considerable interest as to the mechanism by which ghrelin exerts its appetite-stimulating effects, and, in particular, the site of action of ghrelin in the central nervous system (CNS). For example, the neuropeptide Y/Agouti-related peptide (NPY/AGRP) neurons within the arcuate nucleus of the hypothalamus (ARC) are suggested by many t...

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Section: Examples Of Results From Nonresponding Neurons (A) Hyperpolsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ghrelin modulates electrical activity of area postrema neurons

Fry¹,

Ferguson²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Systemic ghrelin administration has been shown to induce the neural expression of c-Fos protein in the SFO, suggesting that ghrelin, released into the circulation, may stimulate SFO neurons (125). Peripherally administered amylin has been shown to induce an anorexigenic effect as a consequence of a reduction in meal size, as has peripheral administration of the amylin-related peptide, salmon calcitonin (21).…”

Section: Anatomical Features Of the Sfomentioning

confidence: 99%

Circulating signals as critical regulators of autonomic state—central roles for the subfornical organ

Smith

Ferguson

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.

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“…If the recorded VMN neuron responded to the cerebellar MN stimulation, its neuronal activity changes in response to one or more stimuli were tested in the following sequence: (1) electrical stimulation of the gastric vagal nerves; (2) glycemia-sensitivity test (Himmi et al 1988;Orsini et al 1991;Yettefti et al 1997), that is, the tested cells that show a specific and significant response, particularly excitation in the case of VMN neurons (Oomura et al 1969;Koizumi and Nishino 1976;Zhu et al 2004), to the stimulation of intravenous glucose administration but not to the injection of normal saline (0.9 % NaCl, 0.5 ml/ kg) and mannitol (0.4 M, 0.5 ml/kg) are identified as glycemia-sensitive neurons; (3) intravenous injection of ghrelin (20 lg/kg; Tocris) (Date et al 2002;Takayama et al 2007), freshly dissolved before the experiment in sterile normal saline (0.9 % NaCl). In some cases, if the VMN neurons responded to both cerebellar MN and gastric vagal stimulation, the neuronal responses to the simultaneous electrical stimulations of the cerebellar MN and gastric vagal nerves were further observed.…”

Section: Stimulation Electrophysiological Recording Data Acquisitiomentioning

confidence: 99%

Medial cerebellar nucleus projects to feeding-related neurons in the ventromedial hypothalamic nucleus in rats

Zhuang

Gao

et al. 2016

Brain Struct Funct

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The cerebellum, a hindbrain motor center, also participates in regulating nonsomatic visceral activities such as feeding control. However, the underlying neural mechanism is largely unknown. Here, we investigate whether the cerebellar medial nucleus (MN), one of the final outputs of the cerebellum, could directly project to and modulate the feeding-related neurons in the ventromedial hypothalamic nucleus (VMN), which has been traditionally implicated in feeding behavior, energy balance, and body weight regulation. The retrograde tracing results show that both GABAergic and glutamatergic projection neurons in the cerebellar MN send direct projections to the VMN. Electrical stimulation of cerebellar MN elicits an inhibitory, excitatory or biphasic response of VMN neurons. Interestingly, the VMN neurons modulated by cerebellar MN afferents not only receive phasic and tonic inputs from the gastric vagal nerves, but also are sensitive to peripheral glycemia and ghrelin signals. Moreover, a summation of inputs from the cerebellar MN and gastric vagal afferents occurs on single glycemia/ghrelin-sensitive neurons in the VMN, and the immunostaining result show that the axons from the cerebellar MN and the projections from the nucleus tractus solitarius, which conveys the gastric vagal inputs to hypothalamus, converge on single VMN glycemia/ghrelin-sensitive neurons. These results demonstrate that the somatic information forwarded by the cerebellar MN, together with the feeding signals from periphery, converge onto single VMN neurons, suggesting that a somatic-visceral integration related to feeding may occur in the VMN and the cerebellum may actively participate in the feeding regulation through the direct cerebellar MN-VMN projections.

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Expression of c-Fos protein in the brain after intravenous injection of ghrelin in rats

Cited by 40 publications

References 23 publications

Ghrelin modulates electrical activity of area postrema neurons

Ghrelin modulates electrical activity of area postrema neurons

Circulating signals as critical regulators of autonomic state—central roles for the subfornical organ

Medial cerebellar nucleus projects to feeding-related neurons in the ventromedial hypothalamic nucleus in rats

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