AUTHOR=Guan Kaiyu , Shan Chunyan , Guo Anqi , Gao Xiang , Li Xi 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1163263

DOI=10.3389/fendo.2023.1163263

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>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 <italic>GHRELIN</italic> as a novel susceptibility gene for human attention-deficit hyperactivity disorder (ADHD), and <italic>ghrelin</italic>-depleted zebrafish (<italic>Danio rerio</italic>) display ADHD-like behaviors. However, the underlying molecular mechanism how ghrelin regulates hyperactivity-like behaviors is not yet known.</p></sec><sec><title>Results</title><p>Here, we performed RNA-sequencing analysis using adult <italic>ghrelin</italic><sup>Δ/Δ</sup>  zebrafish brains to investigate the underlying molecular mechanisms. We found that <italic>gh1</italic> mRNA and genes related to the <italic>gh</italic> signaling pathway were significantly reduced at transcriptional expression levels. Quantitative polymerase chain reaction (qPCR) was performed and confirmed the downregulation of <italic>gh</italic> signaling pathway-related genes in <italic>ghrelin</italic><sup>Δ/Δ</sup> zebrafish larvae and the brain of adult <italic>ghrelin</italic><sup>Δ/Δ</sup> zebrafish. In addition, <italic>ghrelin</italic><sup>Δ/Δ</sup> 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 <italic>ghrelin</italic> mutant zebrafish. </p></sec><sec><title>Conclusion</title><p>Our results indicated that ghrelin may regulate hyperactivity-like behaviors by mediating <italic>gh</italic> signaling pathway in zebrafish. And the protective effect of rhGH on <italic>ghrelin</italic><sup>Δ/Δ</sup> zebrafish hyperactivity behavior provides new therapeutic clues for ADHD patients.</p></sec>