The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Shuyi Deng; Anqi Guo; Zhengwei Huang; Kaiyu Guan; Ya Zhu; Cheekai Chan; Jianfang Gui; Cai Song; Xi Li

doi:10.1016/j.pnpbp.2023.110844

The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Jan 10:128:110844. doi: 10.1016/j.pnpbp.2023.110844. Epub 2023 Aug 26.

Authors

Shuyi Deng¹, Anqi Guo², Zhengwei Huang², Kaiyu Guan³, Ya Zhu⁴, Cheekai Chan⁵, Jianfang Gui⁶, Cai Song⁷, Xi Li⁸

Affiliations

¹ Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
² The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou, Zhejiang 325000, China.
³ Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang 325000, China.
⁴ The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou, Zhejiang 325000, China; State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
⁵ College of Science and Technology, Wenzhou-Kean University, Zhejiang 325000, China.
⁶ State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
⁷ Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China. Electronic address: cai.song@dal.ca.
⁸ The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou, Zhejiang 325000, China. Electronic address: xili@wmu.edu.cn.

PMID: 37640149
DOI: 10.1016/j.pnpbp.2023.110844

Abstract

Inflammation stimulates the hypothalamic-pituitary adrenal (HPA) axis and triggers glial neuroinflammatory phenotypes, which reduces monoamine neurotransmitters by activating indoleamine 2,3-dioxygenase enzyme. These changes can induce psychiatric diseases, including anxiety. Corticotropin releasing hormone receptor 2 (CRHR2) in the HPA axis is involved in the etiology of anxiety. Omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate anxiety through anti-inflammation and HPA axis modulation. However, the underlying molecular mechanism by CRHR2 modulates anxiety and its correlation with neuroinflammation remain unclear. Here, we first constructed a crhr2 zebrafish mutant line, and evaluated anxiety-like behaviors, gene expression associated with the HPA axis, neuroinflammatory response, neurotransmitters, and PUFAs profile in crhr2^+/+ and crhr2^-/- zebrafish. The crhr2 deficiency decreased cortisol levels and up-regulated crhr1 and down-regulated crhb, crhbp, ucn3l and proopiomelanocortin a (pomc a) in zebrafish. Interestingly, a significant increase in the neuroinflammatory markers, translocator protein (TSPO) and the activation of microglia M1 phenotype (CD11b) were found in crhr2^-/- zebrafish. As a consequence, the expression of granulocyte-macrophage colony-stimulating factor, pro-inflammatory cytokines vascular endothelial growth factor, and astrocyte A1 phenotype c3 were up-regulated. While microglia anti-inflammatory phenotype (CD206), central anti-inflammatory cytokine interleukin-4, arginase-1, and transforming growth factor-β were downregulated. In parallel, crhr2-deficient zebrafish showed an upregulation of vdac1 protein, a TSPO ligand, and its downstream caspase-3. Furthermore, 5-HT/5-HIAA ratio was decreased and n-3 PUFAs deficiency was identified in crhr2^-/- zebrafish. In conclusion, anxiety-like behavior displayed by crhr2-deficient zebrafish may be caused by the HPA axis dysfunction and enhanced neuroinflammation, which resulted in n-3 PUFAs and monoamine neurotransmitter reductions.

Keywords: Anxiety disorder; HPA axis; Neuroinflammation; Zebrafish; crhr2.