Institute for Marine Drugs and Nutrition, Zhanjiang City Key Laboratory, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 3452001, Guangdong, China; Graduate Institute of Neural and Cognitive Science, China Medical University and Hospital, Taichung 00001, Taiwan.
Institute for Marine Drugs and Nutrition, Zhanjiang City Key Laboratory, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 3452001, Guangdong, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:384-394. doi: 10.1016/j.pnpbp.2017.08.021. Epub 2017 Aug 26.
Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience research and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we present a new zebrafish model of clinically relevant, prolonged unpredictable strong chronic stress (PUCS). The 5-week PUCS induced overt anxiety-like and motor retardation-like behaviors in adult zebrafish, also elevating whole-body cortisol and proinflammatory cytokines - interleukins IL-1β and IL-6. PUCS also elevated whole-body levels of the anti-inflammatory cytokine IL-10 and increased the density of dendritic spines in zebrafish telencephalic neurons. Chronic treatment of fish with an antidepressant fluoxetine (0.1mg/L for 8days) normalized their behavioral and endocrine phenotypes, as well as corrected stress-elevated IL-1β and IL-6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, PUCS elevated whole-body BDNF levels and the telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in-vivo model of chronic stress, also calling for further cross-species studies of both shared/overlapping and distinct neurobiological responses to chronic stress.
慢性应激是人类焦虑和抑郁的主要发病因素。斑马鱼（Danio rerio）已成为神经科学研究和中枢神经系统药物发现的新型流行模式生物。斑马鱼模拟人类情感障碍的用途也在迅速增加。在这里，我们提出了一种新的斑马鱼模型，用于模拟临床上相关的、长期不可预测的强慢性应激（PUCS）。5 周的 PUCS 诱导成年斑马鱼出现明显的焦虑样和运动迟缓样行为，同时也升高了全身皮质醇和促炎细胞因子-白细胞介素 1β和白细胞介素 6。PUCS 还升高了全身抗炎细胞因子白细胞介素 10 的水平，并增加了斑马鱼端脑神经元树突棘的密度。用抗抑郁药氟西汀（0.1mg/L，8 天）对鱼进行慢性治疗可使它们的行为和内分泌表型正常化，并纠正应激升高的白细胞介素 1β和白细胞介素 6 水平，这与临床和啮齿动物数据相似。bdnf 基因、其两个受体（trkB、p75）和神经胶质标志物 glia 生物标志物 GFAP 的基因在三组中的 CNS 表达均未改变。然而，PUCS 升高了全身 BDNF 水平和端脑树突棘密度（这被氟西汀纠正），因此与慢性应激在啮齿动物中的作用有些不同。总之，这些发现支持斑马鱼作为慢性应激的有用体内模型，也呼吁进一步进行跨物种研究，以了解慢性应激的共享/重叠和独特的神经生物学反应。
