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Ghrelin and Orexin Interact to Increase Meal Size Through a Descending Hippocampus to Hindbrain Signaling Pathway

  • Andrea N. Suarez
    Affiliations
    Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California
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  • Clarissa M. Liu
    Affiliations
    Neuroscience Graduate Program, University of Southern California, Los Angeles, California
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  • Alyssa M. Cortella
    Affiliations
    Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California
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  • Emily E. Noble
    Affiliations
    Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California

    Department of Foods and Nutrition, University of Georgia, Athens, Georgia
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  • Scott E. Kanoski
    Correspondence
    Address correspondence to Scott E. Kanoski, Ph.D., Department of Biological Sciences, University of Southern California, 3560 Watt Way, PED 107, Los Angeles, CA 90089-0652.
    Affiliations
    Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California

    Neuroscience Graduate Program, University of Southern California, Los Angeles, California
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      Abstract

      Background

      Memory and cognitive processes influence the amount of food consumed during a meal, yet the neurobiological mechanisms mediating these effects are poorly understood. The hippocampus (HPC) has recently emerged as a brain region that integrates feeding-relevant biological signals with learning and memory processes to regulate feeding. We investigated whether the gut-derived hormone ghrelin acts in the ventral HPC (vHPC) to increase meal size through interactions with gut-derived satiation signaling.

      Methods

      Interactions between vHPC ghrelin signaling, gut-derived satiation signaling, feeding, and interoceptive discrimination learning were assessed via rodent behavioral neuropharmacological approaches. Downstream neural pathways were identified using transsynaptic virus-based tracing strategies.

      Results

      vHPC ghrelin signaling counteracted the food intake–reducing effects produced by various peripheral biological satiation signals, including cholecystokinin, exendin-4 (a glucagon-like peptide-1 receptor agonist), amylin, and mechanical distension of the stomach. Furthermore, vHPC ghrelin signaling produced interoceptive cues that generalized to a perceived state of energy deficit, thereby providing a potential mechanism for the attenuation of satiation processing. Neuroanatomical tracing identified a multiorder connection from vHPC neurons to lateral hypothalamic area orexin (hypocretin)-producing neurons that project to the laterodorsal tegmental nucleus in the hindbrain. Lastly, vHPC ghrelin signaling increased spontaneous meal size via downstream orexin receptor signaling in the laterodorsal tegmental nucleus.

      Conclusions

      vHPC ghrelin signaling increases meal size by counteracting the efficacy of various gut-derived satiation signals. These effects occur via downstream orexin signaling to the hindbrain laterodorsal tegmental nucleus, thereby highlighting a novel hippocampus-hypothalamus-hindbrain pathway regulating meal size control.

      Keywords

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      • Supersizing the Hippocampus: Ghrelin Effects on Meal Size
        Biological PsychiatryVol. 87Issue 11
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          Most students in the biological and psychological sciences will be able to recall the unforgettable Henry Molaison (H.M.)—an amnesic patient whose characterization revolutionized our understanding of memory. Less well-known, however, is the impact of H.M.’s medial temporal lobectomy on food intake, where his ability to interpret interoceptive hunger signals was greatly diminished. In fact, after fully consuming one meal, when a second was presented to him a mere 60 seconds later, H.M. set about consuming it at an identical rate as the first (1).
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