Ghrelin regulates hyperactivity-like behaviors via growth hormone signaling pathway in zebrafish (Danio rerio)

Kaiyu Guan; Chunyan Shan; Anqi Guo; Xiang Gao; Xi Li

doi:10.3389/fendo.2023.1163263

Ghrelin regulates hyperactivity-like behaviors via growth hormone signaling pathway in zebrafish (Danio rerio)

Front Endocrinol (Lausanne). 2023 Mar 31:14:1163263. doi: 10.3389/fendo.2023.1163263. eCollection 2023.

Authors

Kaiyu Guan^{1

2}, Chunyan Shan², Anqi Guo², Xiang Gao³, Xi Li²

Affiliations

¹ Department of Clinical Psychology, Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang, China.
² The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, Zhejiang, China.
³ Central Laboratory, Scientific Research Department, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Abstract

Introduction: Ghrelin is originally identified as the endogenous ligand for the growth hormone secretagogue receptor (GHSR) and partially acts by stimulating growth hormone (GH) release. Our previous studies have identified GHRELIN as a novel susceptibility gene for human attention-deficit hyperactivity disorder (ADHD), and ghrelin-depleted zebrafish (Danio rerio) display ADHD-like behaviors. However, the underlying molecular mechanism how ghrelin regulates hyperactivity-like behaviors is not yet known.

Results: Here, we performed RNA-sequencing analysis using adult ghrelin ^Δ/Δ zebrafish brains to investigate the underlying molecular mechanisms. We found that gh1 mRNA and genes related to the gh signaling pathway were significantly reduced at transcriptional expression levels. Quantitative polymerase chain reaction (qPCR) was performed and confirmed the downregulation of gh signaling pathway-related genes in ghrelin ^Δ/Δ zebrafish larvae and the brain of adult ghrelin ^Δ/Δ zebrafish. In addition, ghrelin ^Δ/Δ zebrafish displayed hyperactive and hyperreactive phenotypes, such as an increase in motor activity in swimming test and a hyperreactive phenotype under light/dark cycle stimulation, mimicking human ADHD symptoms. Intraperitoneal injection of recombinant human growth hormone (rhGH) partially rescued the hyperactivity and hyperreactive-like behaviors in ghrelin mutant zebrafish.

Conclusion: Our results indicated that ghrelin may regulate hyperactivity-like behaviors by mediating gh signaling pathway in zebrafish. And the protective effect of rhGH on ghrelin ^Δ/Δ zebrafish hyperactivity behavior provides new therapeutic clues for ADHD patients.

Keywords: ADHD; behavioral disorder; ghrelin; growth hormone (GH); zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ghrelin* / genetics
Growth Hormone / genetics
Growth Hormone / metabolism
Human Growth Hormone* / pharmacology
Humans
Signal Transduction*
Zebrafish

Substances

Ghrelin
Growth Hormone
Human Growth Hormone

Grants and funding

This work was supported by grants from the Wenzhou Key Laboratory of Child Psychiatry, Zhejiang Provincial Program in Medicine and Health Sciences and Technology (grant number 2023KY1164 to KG).