Ghrelin improves cognition via activation of the cAMP- CREB signalling pathway in depressed male C57BL/6J mice

Abstract

Background

Depression leads to a cognitive decline and decreases in ghrelin are observed in depression. Ghrelin affects the level of Brain-derived nerve growth factor (BDNF) through the cAMP-CREB signalling pathway, and lower BDNF levels lead to cognitive decline. Therefore, it is reasonable to assume that in depression, lower ghrelin causes a decrease in BDNF levels and cognitive decline though the cAMP- CREB signalling pathway.

Methods

A total of 120 C57BL/6J male mice were randomly divided into six groups of 20 mice: non-depression groups (sham group, ghrelin group, and ghrelin + (D-lys3)-GHRP-6 group) and depression groups (depression group, depression + ghrelin group and depression + ghrelin + (D-lys3)-GHRP group). A depression mouse model was established by injecting normal saline, ghrelin or ghrelin + (D-lys3) -GHRP-6 into the lateral ventricle of each group. Cognition, hippocampal long-term potentiation (LTP), ghrelin mRNA and protein level, BDNF level and CREB level in the hippocampus were detected.

Results

In the depression mouse model groups, all comparison indexes (cognition and hippocampal levels of LTP, ghrelin mRNA and proteins, and BDNF and CREB) had significant negative changes. In the mice with depression, ghrelin or ghrelin + (D-lys3)-GHRP-6 was injected, and all the comparison indicators showed significant positive changes. Supplementation of ghrelin+(D-lys3))-GHRP-6 resulted in more significant positive changes in all comparison indexes than those of ghrelin alone.

Conclusions

In the depression model, lower ghrelin causes hippocampal BDNF to decrease and results in cognitive decline via the cAMP-CREB signalling pathway.

Keywords:

• Depression
• cognition
• ghrelin
• GHSR1a-cAMP-CREB
• BDNF

Acknowledgements

The authors thank the staff of the State Key Laboratory of Management and Control for Complex Systems institute of Automation, Key Laboratory of Chronobiology of Health Ministry in Basic and Forensic School of Sichuan University, the Department of Geriatrics of the third hospital of Mianyang, and all study participants (as well as their legal proxies) for their great contributions.

Disclosure statement

The authors wish to extend their full confidence that there are no conflicts of interest in this research article and that only the fullest integrity was practised in its composition.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 61773381, 61773382], from the Science and Technology Graveness Project of Sichuan Province [grant number 2018JY0131], and from Sichuan provincial health and Family Planning Commission [grant number 17ZD014].