2. Academic Validation
  3. Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models

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

  • Brain Behav Immun. 2021 May;94:327-337. doi: 10.1016/j.bbi.2020.12.029.
Xulai Shi 1,  Kaiyu Guan 1,  Xuyan Peng 2,  Bingru Xu 3,  Xianyong Zhou 1,  Shao Wang 1,  Shengnan Xu 1,  Miaomiao Zheng 1,  Jing Huang 4,  Xiaoyang Wan 5,  Wanchun Guan 3,  Kuan-Pin Su 6,  Minjie Ye 1,  Xiang Gao 7,  Zhan Yin 8,  Xi Li 9
Affiliations

Affiliations

  • 1 The Affiliated Kangning Hospital of Wenzhou Medical University, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, PR China.
  • 2 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, PR China.
  • 3 School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, PR China.
  • 4 Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
  • 5 Institute of Infectious Liver Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
  • 6 Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; An-Nan Hospital, China Medical University, Tainan, Taiwan.
  • 7 Central Laboratory, Scientific Research Department, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address: gaoyangxixi@whu.edu.cn.
  • 8 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, PR China. Electronic address: zyin@ihb.ac.cn.
  • 9 The Affiliated Kangning Hospital of Wenzhou Medical University, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, PR China. Electronic address: xili_ihb@126.com.
PMID: 33412253 DOI: 10.1016/j.bbi.2020.12.029
Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children. The orexigenic hormone ghrelin is important in neuroprotection and neurodevelopment, which may play an important role in psychopathogenesis of ADHD. This study aimed to systematically investigate the genomic and pharmacological manipulations of ghrelin functioning in ADHD-like symptoms in zebrafish models and validated the effects of ghrelin polymorphisms in human subjects with ADHD. We firstly generated ghrelinΔ/Δ zebrafish mutant, which displayed hyperactive, attention deficit-like and impulsive-like behaviors, as well as endophenotypes, mimicking human ADHD. GhrelinΔ/Δ zebrafish exhibited downregulated expression levels of wnt1, wnt3a, wnt5a that are critical for dopaminergic neuron development to possibly regulate their number and spatial organization. Pharmacological blockade of Wnt signaling with XAV939 induced a reduced moving activity and less dopaminergic neurons; whereas, Wnt agonist SB415286 rescued hyperactivity and dopaminergic neuron loss in ghrelinΔ/Δ zebrafish. In addition, we further identified and validated a SNP, rs696217, on orexigenic hormone preproghrelin/ghrelin (T408T, Met72Met) to be associated with a higher risk of ADHD in a case-controlled association study with 248 subjects with ADHD and 208 subjects of healthy controls. Together, our results reveal a novel endogenous role for orexigenic hormone ghrelin in ADHD, which provides insights into genetic regulation and drug screens for the identification of novel treatments of ADHD.

Keywords

Attention deficiency; Dopaminergic neuron; Ghrelin; Hyperactivity; Zebrafish.

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