Deng Shuyi, Guo Anqi, Huang Zhengwei, Guan Kaiyu, Zhu Ya, Chan Cheekai, Gui Jianfang, Song Cai, Li Xi
Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
The Affiliated Kangning Hospital of Wenzhou Medical University, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou, Zhejiang 325000, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Jan 10;128:110844. doi: 10.1016/j.pnpbp.2023.110844. Epub 2023 Aug 26.
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.
炎症刺激下丘脑 - 垂体 - 肾上腺（HPA）轴并触发神经胶质细胞的神经炎症表型，这会通过激活吲哚胺2,3 - 双加氧酶来减少单胺类神经递质。这些变化可诱发包括焦虑症在内的精神疾病。HPA轴中的促肾上腺皮质激素释放激素受体2（CRHR2）参与焦虑症的病因。ω(n)-3多不饱和脂肪酸（PUFAs）可通过抗炎和调节HPA轴来减轻焦虑。然而，CRHR2调节焦虑的潜在分子机制及其与神经炎症的相关性仍不清楚。在此，我们首先构建了crhr2斑马鱼突变系，并评估了crhr2和野生型斑马鱼的焦虑样行为、与HPA轴相关的基因表达、神经炎症反应、神经递质和PUFAs谱。crhr2缺陷降低了斑马鱼的皮质醇水平，上调了crhr1，下调了crhb、crhbp、ucn 3l和阿黑皮素原a（pomc a）。有趣的是，在crhr2斑马鱼中发现神经炎症标志物转位蛋白（TSPO）显著增加以及小胶质细胞M1表型（CD11b）激活。结果，粒细胞 - 巨噬细胞集落刺激因子、促炎细胞因子血管内皮生长因子和星形胶质细胞A1表型c3的表达上调。而小胶质细胞抗炎表型（CD206）、中枢抗炎细胞因子白细胞介素 - 4、精氨酸酶 - 1和转化生长因子 - β下调。同时，crhr2缺陷的斑马鱼显示TSPO配体电压依赖性阴离子通道蛋白1（vdac1）及其下游半胱天冬酶 - 3上调。此外，在crhr2斑马鱼中5 - 羟色胺/5 - 羟吲哚乙酸（5 - HT/5 - HIAA）比值降低且n - 3 PUFAs缺乏。总之，crhr2缺陷的斑马鱼表现出的焦虑样行为可能是由HPA轴功能障碍和神经炎症增强引起的，这导致了n - 3 PUFAs和单胺类神经递质减少。
