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Involvement of Scratch2 in GalR1-mediated depression-like behaviors in the rat ventral periaqueductal gray [Neuroscience]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.1922586118
Yutao Yang, Yueting Li, Bo Liu, Chenchen Li, Zijin Liu, Jiahui Deng, Hanjiang Luo, Xiaoxiao Li, Jinjin Wu, Hui Li, Chuan-Yue Wang, Ming Zhao, Haohao Wu, Francois Lallemend, Per Svenningsson, Tomas G. M. Hökfelt, Zhi-Qing David Xu

Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from −250 to −220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.



中文翻译:

Scratch2 参与大鼠腹侧导水管周围灰质中 GalR1 介导的抑郁样行为 [神经科学]

慢性轻度应激 (CMS) 后,大鼠腹侧导水管周围灰质 (vPAG) 中的甘丙肽受体 1 (GalR1) 转录水平升高,并且与抑郁样行为有关。为了探索 GalR1 表达升高的潜在机制,我们进行了体外分子生物学实验和体内动物行为实验。发现GalR1基因的上游受限区域,从 -250 到 -220,包含一个 E-box 并在GalR1启动子活性中起负面作用。转录因子 Scratch2 与 E-box 结合以下调 GalR1启动子活性并降低GalR1 的表达水平基因。Scratch2的表达在CMS大鼠的vPAG中显着降低。重要的是,vPAG 中 Scratch2 的局部敲低导致相同区域中 GalR1 的表达升高,以及类似抑郁的行为。RNAscope 分析显示GalR1 mRNA 与Scratch2 在GABA 和谷氨酸神经元中一起表达。将这些数据放在一起,我们的研究进一步支持 GalR1 参与情绪控制,并表明 Scratch2 通过抑制vPAG 中的GalR1基因,作为抑郁样行为的调节剂发挥作用。

更新日期:2021-06-10
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