Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling

Biol Psychiatry. 2013 May 1;73(9):915-23. doi: 10.1016/j.biopsych.2012.07.002. Epub 2012 Aug 11.


Background: The stomach-derived hormone ghrelin drives higher-order feeding processes related to food reward and food seeking via central nervous system signaling at its receptor (GHSR1A). The specific nuclei mediating these effects are only partially understood. Here, we use a rat model to examine whether ghrelin signaling in the ventral subregion of the hippocampus (VHPC), a brain substrate of recent interest in energy balance control, affects learned and motivational aspects of feeding behavior.

Methods: The effects of VHPC ghrelin administration were examined on feeding-relevant behavioral paradigms, including meal pattern analysis, operant lever pressing for sucrose, and conditioned stimulus-induced feeding. The intracellular signaling and downstream neuronal pathways stimulated by VHPC GHSR1A activation were assessed with immunoblot analysis and behavioral pharmacology.

Results: Ghrelin delivery to the VHPC but not the dorsal hippocampus increased food intake primarily by increasing meal frequency. Intra-VHPC ghrelin delivery also increased willingness to work for sucrose and increased spontaneous meal initiation in nondeprived rats after the presentation of a conditioned stimulus that previously signaled meal access when the rats were food-restricted. The food intake enhancing effects of VHPC ghrelin were blocked by co-administration of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Immunoblot analyses provided complementary support for ghrelin activated PI3K-Akt signaling in the VHPC and revealed that this activation is blunted with high-fat diet consumption. Other immunoblot results show that VHPC GHSR1A signaling activates downstream dopaminergic activity in the nucleus accumbens.

Conclusions: These findings illuminate novel neuronal and behavioral mechanisms mediating ghrelinergic control of cognitive aspects of feeding control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromones / pharmacology
  • Eating / drug effects
  • Eating / physiology
  • Enzyme Inhibitors / pharmacology
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology*
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Learning / drug effects
  • Learning / physiology
  • Male
  • Morpholines / pharmacology
  • Motivation / drug effects
  • Motivation / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Ghrelin / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Chromones
  • Enzyme Inhibitors
  • Ghrelin
  • Ghsr1a protein, rat
  • Morpholines
  • Receptors, Ghrelin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt