Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models

Shi, Xiaojian; Guan, Kaiyu; Peng, Xuyan; Xu, Bingru; Zhou, Xian-Yong; Shao, Wei; Xu, Shengnan; Zheng, Miaomiao; Huang, Jing; Wan, Xiaoyang; Guan, Wanchun; Su, Kuan‐Pin; Ye, Minjie; Gao, Xiang; Yin, Zhan; Li, Xi

doi:10.1016/j.bbi.2020.12.029

Cited by 10 publications

(9 citation statements)

References 55 publications

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“…Multiple roles of Wnt/β-catenin signaling in hypothalamic development have also been uncovered in mammalian systems 50 , 51 . It will be interesting to learn how Wnt/β-catenin signaling is integrated with other signaling pathways that have recently been shown to be active in DA progenitors of the zebrafish hypothalamus, including Shh signaling, Ghrelin signaling, as well as microRNAs 52 – 54 . In zebrafish, loss of function of ghrelin leads to a downregulation of Wnt/β-catenin genes and concomitantly to a reduction of DA neurons 54 .…”

Section: Discussionmentioning

confidence: 99%

“…It will be interesting to learn how Wnt/β-catenin signaling is integrated with other signaling pathways that have recently been shown to be active in DA progenitors of the zebrafish hypothalamus, including Shh signaling, Ghrelin signaling, as well as microRNAs 52 – 54 . In zebrafish, loss of function of ghrelin leads to a downregulation of Wnt/β-catenin genes and concomitantly to a reduction of DA neurons 54 . Interestingly, pharmacological activation of the Wnt/β-catenin signaling pathway rescues the DA neuron loss in ghrelin mutants, demonstrating a functional link between Ghrelin and Wnt/β-catenin signaling in DA neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish

Westphal

Panza

Kastenhuber

et al. 2022

Sci Rep

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Wnt/β-catenin signaling contributes to patterning, proliferation, and differentiation throughout vertebrate neural development. Wnt/β-catenin signaling is important for mammalian midbrain dopaminergic neurogenesis, while little is known about its role in ventral forebrain dopaminergic development. Here, we focus on the A11-like, Otp-dependent diencephalospinal dopaminergic system in zebrafish. We show that Wnt ligands, receptors and extracellular antagonist genes are expressed in the vicinity of developing Otp-dependent dopaminergic neurons. Using transgenic Wnt/β-catenin-reporters, we found that Wnt/β-catenin signaling activity is absent from these dopaminergic neurons, but detected Wnt/β-catenin activity in cells adjacent to the caudal DC5/6 clusters of Otp-dependent dopaminergic neurons. Pharmacological manipulations of Wnt/β-catenin signaling activity, as well as heat-shock driven overexpression of Wnt agonists and antagonists, interfere with the development of DC5/6 dopaminergic neurons, such that Wnt/β-catenin activity positively correlates with their number. Wnt/β-catenin activity promoted dopaminergic development specifically at stages when DC5/6 dopaminergic progenitors are in a proliferative state. Our data suggest that Wnt/β-catenin signaling acts in a spatially and temporally restricted manner on proliferative dopaminergic progenitors in the hypothalamus to positively regulate the size of the dopaminergic neuron groups DC5 and DC6.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish

Westphal

Panza

Kastenhuber

et al. 2022

Sci Rep

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Section: Introductionmentioning

confidence: 99%

“…Our previous study identified GHRELIN is a new susceptibility gene for human ADHD patients by sequencing the PREPROGHRELIN/GHRELIN gene of 248 ADHD patients and 208 healthy children (32). Ghrelin-deficient zebrafish clearly displayed ADHD-like behaviors, such as hyperactivity, inattention, defective learning and memory and impulsive-like impaired, with dysfunctional dopaminergic system (32). GHRELIN is a brain-gut peptide that acts as an endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R1a) and mediates the various functions in nervous system, such as memory formation, hippocampal neurogenesis adiposity, energy homeostasis, sleep and anti-anxiety (33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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IntroductionGhrelin 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.ResultsHere, we performed RNA-sequencing analysis using adult ghrelinΔ/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 ghrelinΔ/Δ zebrafish larvae and the brain of adult ghrelinΔ/Δ zebrafish. In addition, ghrelinΔ/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. ConclusionOur results indicated that ghrelin may regulate hyperactivity-like behaviors by mediating gh signaling pathway in zebrafish. And the protective effect of rhGH on ghrelinΔ/Δ zebrafish hyperactivity behavior provides new therapeutic clues for ADHD patients.

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“…Given this extensive range of roles, dysregulation of Wnt signaling could have pathological effects on neurodevelopment 47 . Previous ndings have afforded new hypotheses: Apart from the well-recognized multifactorial ADHD etiological factors, recent evidence proposes that the interface between genetic and environmental factors and particularly Wnt signaling pathways might signi cantly contribute to ADHD pathophysiology 10,34,48,49,50,51 .…”

Section: Introductionmentioning

confidence: 99%

Proteomics data reveals Wnt signaling involvement in the hippocampal-dependent behavioral impairment in THRSP-overexpressing attention-deficit/hyperactivity disorder mouse model

Custodio

Kim

et al. 2022

Preprint

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Despite the predominance and high heritability of attention-deficit/hyperactivity disorder (ADHD), its etiology remains unclear. Preclinical and clinical evidence partially implicates impaired limbic system function, particularly in the hippocampus (HPC). Children diagnosed with ADHD often struggle with deficits in executive function, temporal processing, and visuospatial memory, the defining hallmarks of the predominantly inattentive presentation (ADHD-PI), which is subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structure to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal tissues from a mouse model overexpressing (OE) thyroid hormone-responsive protein (THRSP) with defining characteristics of ADHD-PI were utilized for proteomic analyses. Integrated proteomics and network analysis revealed altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal cell proliferation (BrdU) and neurogenic marker expression (i.e., NEU-N, GFAP), markers of neural stem cell (NSC) activity. In addition, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity.

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Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models

Cited by 10 publications

References 55 publications

Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish

Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish

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

Proteomics data reveals Wnt signaling involvement in the hippocampal-dependent behavioral impairment in THRSP-overexpressing attention-deficit/hyperactivity disorder mouse model

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