Study shows ghrelin improves learning and memory, but some researchers remain unconvinced
By Melissa Lee Phillips | February 20, 2006
The neurohormone ghrelin, best known for its role in appetite and energy metabolism, also influences learning and memory, according to a new study in Nature Neuroscience. Specifically, Sabrina Diano of Yale University School of Medicine and her colleagues found that high levels of ghrelin in rodents can alter hippocampal morphology and improve performance on memory and learning tasks. This pattern may have provided an evolutionary advantage, the authors speculate, by boosting memory skills during food searches when animals are hungry.
The study doesn?t prove that normal levels of circulating ghrelin control learning and memory, said Robert Steiner of the University of Washington in Seattle, but ?it still is a pretty interesting concept? that ghrelin can modulate hippocampal function and memory performance. ?It establishes a nice platform for further investigation, particularly in the pharmacological realm,? added Steiner, who was not involved in the research.
Ghrelin is released primarily from stomach epithelial cells when the stomach is empty and binds to receptors in several areas of the body. It stimulates the release of growth hormone and also acts at hypothalamic feeding centers to increase hunger. Ghrelin receptors have also been found in many brain areas outside the hypothalamus, Steiner said, including in the hippocampus.
Previous work has pointed to a correlation between ghrelin and memory retention tasks, said Yogendra Shrestha of the University of Georgia in Athens, but Diano and her co-workers have ?gone into great detail? by examining changes in anatomy and electrophysiology.
The researchers first confirmed that peripheral ghrelin crosses the blood-brain barrier and enters the hippocampal formation. They next found that the density of dendritic spine synapses in the hippocampus?a measure of synaptic plasticity that correlates with spatial memory and learning?was significantly higher in mice that were injected with ghrelin versus non-injected controls.
Ghrelin knockout mice also had significantly fewer dendritic spines than did their wild-type littermates. When ghrelin knockouts were injected with ghrelin, however, their spine synapse density increased. The authors also found that ghrelin treatment increased long-term potentiation (LTP) in hippocampal slice preparations.
Diano and her colleagues then tested the effects of ghrelin administration in several learning and memory tasks. First, injecting rats peripherally with ghrelin or a ghrelin-receptor agonist improved their performance on a maze task that depends on hippocampal function. Next, injecting ghrelin into the cerebral ventricles after training on an avoidance task improved task learning not only in wild-type mice but also in mice that display the pathological and cognitive symptoms of Alzheimer?s disease. Lastly, the authors found that ghrelin-knockout mice fare worse during object recognition tasks that employ the hippocampus, but improve after peripheral ghrelin administration.
The results are ?quite surprising,? according to Michael Cowley of Oregon Health & Science University in Portland, who didn?t participate in this study. Showing that learning improves with ghrelin supplementation even in wild-type animals suggests that, ?in situations of fasting, you can get increases in this kind of performance in normal animals,? Cowley said.
Learning and memory may be enhanced by high levels of ghrelin during food deprivation because animals need increased cognitive skills to track down food sources, Diano told The Scientist.
However, Steiner cautioned that the researchers injected a concentration of ghrelin that?s several orders of magnitude above what would be found in the bloodstream, which means that normal fluctuations in ghrelin due to food deprivation may have nothing to do with learning or memory.
Ghrelin is also produced in the brain, suggesting that differences seen in ghrelin knockouts may be due to disrupted ghrelin expression there, rather than in the stomach, Christian Broberger of the Karolinska Institute in Stockholm, also not a co-author, told The Scientist in an Email.
It?s also a bit surprising that ghrelin would have positive effects on learning and memory, according to David E. Cummings of the University of Washington, because the hormone insulin has also been shown to improve learning and memory, and ghrelin and insulin usually have opposite effects.
Even if ghrelin fluctuations do not normally influence memory, Steiner said, high doses of ghrelin or an analog could still make good candidates for treatment of age-related memory problems. ?I?m more enthusiastic about the pharmacologic and pharmacotherapeutic implications of the study than I am about whether or not the physiological arguments that they developed are true.?
Melissa Lee Phillips
Links within this article
J. Kling, ?Elusive ligand ghrelin could have numerous roles,? The Scientist, June 10, 2002.
S. Blackman, ?The hunger hormone unharnessed, The Scientist, October 6, 2003.
S. Diano et al., ?Ghrelin controls hippocampal spine synapse density and memory performance,? Nature Neuroscience, February 19, 2006.
A. J. van der Lely et al., ?Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin,? Endocrine Reviews, June 2004.
M. Kojima et al., ?Ghrelin is a growth-hormone-releasing acylated peptide from stomach,? Nature, December 9, 1999.
V. P. Carlini et al., ?Ghrelin increases anxiety-like behavior and memory retention in rats,? Biochemical and Biophysical Research Communications, December 20, 2002.
N. Burgess et al., ?The human hippocampus and spatial and episodic memory,? Neuron, August 15, 2002.
K. Heyman, ?Neurophysiology: Dust clearing on the long-term potentiation debate,? The Scientist, May 23, 2005.
M.A. Cowley et al., ?The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis,? Neuron, February 20, 2003.
David E. Cummings