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      Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways

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          Abstract

          Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling.

          DOI: http://dx.doi.org/10.7554/eLife.11190.001

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          Eating can occur for many different reasons. We often eat not simply because we are hungry, but because we have learned to eat at specific times of day or in response to factors in our environments (for example, an advert that reminds of us of something tasty). Despite this, few researchers have investigated how biological signals from the gut communicate with the brain to enable this type of learned, or “conditioned”, feeding behavior.

          Brain cells called neurons communicate with each other in specific circuits that can cross between different brain regions. Hsu et al. have now developed a “disconnection neuropharmacology” approach, which alters whether the neurons in different brain regions can communicate with each other, to investigate the effects signaling molecules have on brain activity and behavior. Using this approach in rats revealed a new circuit in the brain that controls learned feeding behavior through ghrelin, a hormone that is released from the stomach and increases appetite.

          Hsu et al. found that the hippocampus, a brain region important for learning and memory control, uses ghrelin as a signal to engage in learned feeding behavior. Neurons in the hippocampus that respond to ghrelin communicate with other neurons in a region of the brain called the lateral hypothalamus (known for its role in feeding) that produce a signaling molecule called orexin. This circuit therefore links memory and feeding behavior.

          Future work will investigate the neural circuits between the hippocampus and other brain regions that are important for feeding behavior, and the hormones that are important for triggering activity in these circuits.

          DOI: http://dx.doi.org/10.7554/eLife.11190.002

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          Most cited references79

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          Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

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            Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

            The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
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              Differential expression of orexin receptors 1 and 2 in the rat brain.

              Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability. Copyright 2001 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                2050-084X
                15 December 2015
                2015
                : 4
                : e11190
                Affiliations
                [1 ]deptHuman and Evolutionary Biology Section, Department of Biological Sciences , University of Southern California , Los Angeles, United States
                [2 ]deptNeuroscience Program , University of Southern California , Los Angeles, United States
                [3 ]deptNeurobiology Section, Department of Biological Sciences , University of Southern California , Los Angeles, United States
                [4]Howard Hughes Medical Institute, University of Washington , United States
                [5]Howard Hughes Medical Institute, University of Washington , United States
                Author notes
                Article
                11190
                10.7554/eLife.11190
                4695382
                26745307
                49ca045f-c127-471c-8ce2-fabcb63a9a68
                © 2015, Hsu et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 27 August 2015
                : 06 November 2015
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: DK097147
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006034, University of Southern California;
                Award ID: USC Diabetes and Obesity Research Institute Pilot Grant
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: DK102478
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: DK104897
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                2.5
                A communication pathway linking memory processing and feeding behavior exists between the gut hormone ghrelin, the hippocampus and the hypothalamic neuropeptide orexin.

                Life sciences
                appetite,learning,obesity,ventral hippocampus,ghsr,feeding,rat
                Life sciences
                appetite, learning, obesity, ventral hippocampus, ghsr, feeding, rat

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