Institute of Biology, Leiden University, Leiden, The Netherlands.
Institute of Biology, Leiden University, Leiden, The Netherlands.
Gen Comp Endocrinol. 2020 Jun 1;292:113461. doi: 10.1016/j.ygcen.2020.113461. Epub 2020 Mar 17.
Previously, adult zebrafish with a mutation in the gene encoding the glucocorticoid receptor (Gr) were demonstrated to display anxiety- and depression-like behavior that could be reversed by treatment with antidepressant drugs, suggesting that this model system could be applied to study novel therapeutic strategies against depression. Subsequent studies with zebrafish larvae from this gr line and a different gr mutant have not confirmed these effects. To investigate this discrepancy, we have analyzed the anxiety-like behavior in 5 dpf gr larvae using a dark/tapping stimulus test and a light/dark preference test. In addition, gr adult fish were subjected to an open field test. The results showed that in larvae the mutation mainly affected general locomotor activity (decreased velocity in the dark/tapping stimulus test, increased velocity in the light/dark preference test). However, parameters considered specific readouts for anxiety-like behavior (response to dark/tapping stimulus, time spent in dark zone) were not altered by the mutation. In adults, the mutants displayed a profound increase in anxiety-like behavior (time spent in outer zone in open field test), besides changes in locomotor activity (decreased velocity, increased angular velocity and freezing time). We conclude that the neuronal circuitry involved in anxiety- and depression-like behavior is largely affected by deficient Gr signaling in adult fish but not in larvae, indicating that this circuitry only fully develops after the larval stages in zebrafish. This makes the zebrafish an interesting model to study the ontology of anxiety- and depression-related pathology which results from deficient glucocorticoid signaling.
先前，研究人员发现编码糖皮质激素受体（Gr）的基因突变的成年斑马鱼表现出焦虑和抑郁样行为，这些行为可以通过抗抑郁药物治疗得到逆转，这表明这种模型系统可用于研究针对抑郁症的新治疗策略。随后，来自该 gr 系和另一个不同 gr 突变体的斑马鱼幼虫研究并未证实这些效果。为了研究这种差异，我们使用黑暗/敲击刺激试验和光/暗偏好试验分析了 5 dpf gr 幼虫的焦虑样行为。此外，gr 成年鱼还接受了旷场试验。结果表明，在幼虫中，突变主要影响一般运动活动（黑暗/敲击刺激试验中的速度降低，光/暗偏好试验中的速度增加）。然而，被认为是焦虑样行为特定指标的参数（对黑暗/敲击刺激的反应、在黑暗区域花费的时间）并未因突变而改变。在成年鱼中，突变体表现出明显的焦虑样行为增加（旷场试验中外圈停留时间），除了运动活动的变化（速度降低、角速度增加和冻结时间增加）。我们得出结论，参与焦虑和抑郁样行为的神经元回路在成年鱼中由于 Gr 信号传导缺陷而受到很大影响，但在幼虫中则不受影响，这表明该回路仅在斑马鱼的幼虫阶段后才完全发育。这使得斑马鱼成为研究因糖皮质激素信号传导缺陷而导致的焦虑和抑郁相关病理学发生机制的有趣模型。
