Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice
Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice
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DOI：
10.1038/nature04250
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发表时间：
2005-12-01
期刊：
影响因子：
64.8
通讯作者：
Barlow, C
中科院分区：
文献类型：
--
作者：
Hovatta, I;Tennant, RS;Barlow, C
焦虑和恐惧是对威胁情境的正常情绪反应。在人类焦虑症中——例如惊恐障碍、强迫症、创伤后应激障碍、社交恐惧症、特定恐惧症和广泛性焦虑障碍——这些反应被夸大了。调节正常和病理性焦虑所涉及的分子机制大多尚不清楚。然而，不同近交系小鼠的可获得性提供了一个极好的模型系统，可用于研究某些行为表型的遗传学（1 - 3）。在此我们报告，通过对6种近交系小鼠进行行为分析，并结合对几个脑区的定量基因表达谱分析，鉴定出17个基因，其表达模式与焦虑样行为表型相关。为了确定其中两个基因——乙二醛酶1和谷胱甘肽还原酶1——是否在焦虑的产生中起因果作用，我们利用慢病毒介导的基因转移进行了基因操作。在小鼠大脑中局部过表达这些基因导致焦虑样行为增加，而通过RNA干扰局部抑制乙二醛酶1的表达则减少了焦虑样行为。这两个基因都参与氧化应激代谢，将该途径与焦虑相关行为联系起来。
Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders - such as panic disorder, obsessive - compulsive disorder, post- traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder - these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes(1-3). Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety- like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus- mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety- like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety- like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety- related behaviour.