Summary: The hunger hormone ghrelin doesn’t just influence where and when animals eat, it also appears to have an impact on memory. Disrupting signaling of ghrelin to the vagus nerve caused rats to forget they had just eaten, even though the animals remembered they had just had access to food. Findings suggest disrupted ghrelin signaling could negatively impact episodic memory.
A hormone that influences when and how frequently animals eat also appears to affect memory, USC scientists have found.
The study was published in the journal Current Biology on Sept. 17.
Animals and humans have the hormone ghrelin in their stomachs. Ghrelin tells animals, as well as humans, when they are hungry and helps regulate their metabolism, but scientists have never been certain how exactly it works.
To learn more about how ghrelin influences hunger, metabolism and memory, researchers at the USC Dornsife College of Letters, Arts and Sciences collaborated with international scientists on a study on rats.
They disrupted the ability of the ghrelin hormone to communicate to the vagus nerve, a nerve that signals from the gut to the brain, and then monitored the impact on their feeding and cognitive behaviors.
The rats were not anxious, but they began eating more frequently, said the study’s lead and corresponding author Scott Kanoski, an Associate Professor of Biological Sciences at USC Dornsife.
The lack of ghrelin signaling to the vagus nerve “not only disrupted their blood glucose regulation, but they also gained more weight,” Kanoski said.
“But it didn’t seem to be affecting how much food they ate,” he added. Instead, “they increased their frequency of eating, so that they consumed more meals and they compensated for that by reducing the size of their meals.”
“We think that the increased eating frequency is related to their memory impairment. Memory from when you last ate will influence how soon you eat again. It led the rats in our study to eat sooner,” said Kanoski.
Although the rats were able to remember where they had gotten food, they appeared to have forgotten that they had just eaten. Their stomachs were also slower to empty.
“The animals were impaired in a certain type of memory, called episodic memory,” said study co-author Elizabeth Davis who was a post-doctoral researcher in Kanoski lab at USC Dornsife. “This is the type of memory that helps you remember your first day of school, or what you ate for breakfast yesterday?
Davis said scientists are trying to learn more about ghrelin signaling through the vagus nerve because it may help researchers develop better therapies for metabolic-related diseases such as obesity and diabetes or other metabolic diseases, as well as others such as epilepsy and Alzheimer’s disease.
However, “a great deal of further research will be needed to uncover how manipulation of ghrelin signaling through the vagus nerve may be valuable in human medicine,” said Davis, who recently left USC for a private pharmaceutical company after completing her post-doctoral degree in biological sciences.
Other co-authors included Hallie Wald at the University of Pennsylvania; Andrea Suarez at USC Dornsife; Jasenka Zubcevic and Guillaume de Lartigue at University of Florida-Gainesville; Clarissa Liu at USC Dornsife; Anna Kamitakahara at Children’s Hospital of Los Angeles; Jaimie Polson at University of Sydney; and Myrtha Arnold at ETH Zurich.
•VAN ghrelin receptor (GHSR) knockdown disrupts meal patterns and metabolic indices
•VAN signaling is required for the hyperphagic effects of ghrelin in the dark cycle
•Gut-restricted circulating ghrelin increases VAN firing rate via VAN GHSR
Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the control of feeding behavior and metabolism . Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including affective motivational behaviors and hippocampus (HPC)-dependent memory [2, 3, 4, 5]. VANs, located in nodose ganglia, express receptors for various gut-derived peptide signals; however, the function of these receptors with regard to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (GHSR) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNAi-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPC-dependent contextual episodic memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or general activity levels. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory.