Ghrelin Increases Food Intake via Descending Hippocampus to Hindbrain Signalling Pathway

Post by Amanda McFarlan

What's the science?

Ghrelin is a gut-derived hormone that plays a critical role in feeding behavior by stimulating the appetite. The ghrelin receptor can be found in regions of the hippocampus and recently, it has been shown that activating the ghrelin receptor in the ventral hippocampus results in an increase in food intake. However, the underlying mechanisms that mediate feeding behavior are still unknown. This week in Biological Psychiatry, Suarez and colleagues investigated the role of ghrelin signalling in the ventral hippocampus in mediating food intake.

How did they do it?

To investigate the role of hippocampal ghrelin signalling, the authors implanted cannulas bilaterally in the ventral hippocampus in adult male rats. After food-restricting the rats for 24 hours, they delivered an injection of artificial cerebrospinal fluid (as a control) or a subthreshold dose of ghrelin (no effect on feeding behaviours alone) through the cannulas. Approximately 45 minutes after the injection, they performed either an intraperitoneal injection of a satiation-promoting drug or a nonnutritive oral gavage of fiber to physically expand the stomach. The rats were given access to food following the intraperitoneal injection or gavage and their food intake was recorded for up to 4 hours. Then, the authors used a deprivation intensity discrimination task to train two groups of rats to use internal cues about their hunger and satiety levels as a discriminative stimulus for a sugar reward. The first group of rats was trained to anticipate a reward after 24 hours of food restriction, while the second group was trained to anticipate a reward with no food restriction. After the training, both groups of rats underwent two test days following a period of no food restriction. On the test days, the rats received a delivery of artificial cerebrospinal fluid (control) or ghrelin in the ventral hippocampus via the cannulas (with the order counterbalanced) 1 hour prior to being placed in an operant chamber to record their appetitive behavior. Next, to identify the downstream targets of the ventral hippocampal → lateral hypothalamic area projections, the authors targeted the expression of Cre-recombinase to neurons in the ventral hippocampus and their first-order targets and targeted the expression of an anterograde tracer (traces neurons from their source to their target) tagged with tdTomato in the lateral hypothalamic area. They performed immunohistochemistry and fluorescence in situ hybridization to map the axons from lateral hypothalamic area projections and determine their neuronal targets.

What did they find?

The authors determined that administering a subthreshold dose of ghrelin to the ventral hippocampus in 24-hour food-restricted rats significantly attenuated the reduction in food intake following the administration of satiation-promoting drugs or oral fiber gavage compared to controls. Since the satiation-promoting drugs targeted either the paracrine (vagal) or non-vagal endocrine pathways, these findings indicate that ghrelin signalling within the ventral hippocampus may act on both paracrine and endocrine pathways to mediate food intake. Next, the authors revealed that, following the administration of ghrelin in the ventral hippocampus, the group of rats that were trained to anticipate a reward after 24 hours of food restriction had an increase in appetitive behaviors compared to controls. In contrast, the group of rats that were trained to anticipate a reward with no food restriction had a decrease in appetitive behaviors compared to controls. These findings suggest that ghrelin signalling in the ventral hippocampus may override satiety-inducing mechanisms by producing internal cues that signal a low energy state similar to being food-restricted for 24 hours. The authors also found that the ghrelin receptor is most commonly expressed in glutamatergic neurons in the pyramidal layer of the ventral hippocampus. Further, they showed that a subset of tdTomato-positive projection neurons in the lateral hypothalamic area was co-localized with the expression of orexin (a neuropeptide that promotes food intake) and had axon terminals that targeted the laterodorsal tegmental nucleus. They used fluorescent in situ hybridization to determine that a large population of neurons in the laterodorsal tegmental nucleus in the hindbrain have a co-localized expression of the orexin-1 receptor and the glucagon-like peptide-1 receptor (previously shown to be important for reducing food intake). Together, these findings suggest that glutamatergic neurons in the ventral hippocampus that express the ghrelin receptor project to orexin neurons in the lateral hypothalamic area, which in turn target neurons in the laterodorsal tegmental nucleus in the hindbrain to regulate food intake.

What's the impact?

This is the first study to show that ghrelin signalling in the ventral hippocampus decreases the efficacy of satiation and satiety-promoting signals that target endocrine pathways in the periphery. The authors also identified orexin neurons in the lateral hypothalamic area as the downstream targets of ghrelin receptor-expressing neurons in the ventral hippocampus. Together, these findings provide insight into the neural pathways and mechanisms involved in hippocampal-mediated control of feeding behavior via ghrelin signalling.

Suarez et al. Ghrelin and orexin interact to increase meal size through a descending hippocampus to hindbrain signalling pathway (2019). Access the original scientific publication here.