Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation.
Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation.
复制标题
DOI：
10.1016/j.biopsych.2008.08.005
复制
发表时间：
2009-01-15
影响因子：
10.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Polter A;Yang S;Zmijewska AA;van Groen T;Paik JH;Depinho RA;Peng SL;Jope RS;Li X
哺乳动物FoxO转录因子调节多种生理过程。新出现的证据表明BDNF和锂都抑制FoxO的活性，这表明FoxO在调节情绪相关行为中的潜在作用。在这里，我们研究了大脑FoxO1和FoxO3a是否可以被血清素和抗抑郁药调节，以及它们的基因缺失是否会影响行为。用d-芬氟拉明或抗抑郁药丙咪嗪治疗C57BL/6小鼠，以增加脑血清素能活性。通过免疫印迹分析检测脑FoxO1和FoxO3a的磷酸化和亚细胞定位功能状态。FoxO1和FoxO3a缺陷小鼠的行为表现通过高架+迷宫测试、强迫游泳测试、悬尾测试和开阔场地测试进行评估。d-芬氟拉明增加5 -羟色胺能活性，显著增加大脑多个区域FoxO1和FoxO3a的磷酸化，降低FoxO1和FoxO3a的核表达。d-芬氟拉明的作用是通过PI3K/Akt信号通路介导的。慢性而非急性抗抑郁药丙咪嗪治疗也增加了脑FoxO1和FoxO3a的磷酸化。当FoxO1被选择性地从大脑中删除后，小鼠的焦虑程度降低。相比之下，foxo3a缺陷小鼠表现出明显的抗抑郁样行为。foxo可能是焦虑和情绪障碍治疗的转录靶点。尽管FoxO1和FoxO3a在生理和功能上存在相关性，但它们影响着与焦虑和抑郁相关的不同行为过程。本研究的发现揭示了FoxOs在大脑中的重要新作用，并为进一步研究FoxOs如何控制情绪和焦虑障碍提供了分子框架。
The mammalian FoxO transcription factors function to regulate diverse physiological processes. Emerging evidence that both BDNF and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant, and whether their genetic deletion affects behaviors. C57BL/6 mice were treated with d-fenfluramine to increase brain serotonergic activity, or with the antidepressant imipramine. The functional status of brain FoxO1 and FoxO3a was audited by immunoblot analysis for phosphorylation and subcellular localization. The behavioral manifestations in FoxO1 and FoxO3a deficient mice were assessed via the Elevated Plus Maze Test, Forced Swim Test, Tail Suspension Test, and Open Field Test. Increasing serotonergic activity by d-fenfluramine strongly increased phosphorylation of FoxO1 and FoxO3a in several brain regions, and reduced nuclear FoxO1 and FoxO3a. The effect of d-fenfluramine was mediated by the PI3K/Akt signaling pathway. Chronic, but not acute, treatment with the antidepressant imipramine also increased the phosphorylation of brain FoxO1 and FoxO3a. When FoxO1 was selectively deleted from brain, mice displayed reduced anxiety. In contrast, FoxO3a-deficient mice presented with a significant antidepressant-like behavior. FoxOs may be a transcriptional target for anxiety and mood disorder treatment. Despite their physical and functional relatedness, FoxO1 and FoxO3a influence distinct behavioral processes linked to anxiety and depression. Findings in this study reveal important new roles of FoxOs in brain and provide a molecular framework for further investigation of how FoxOs may govern mood and anxiety disorders.
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
FOXO转录因子直接激活BIM基因表达并促进交感神经元中的凋亡。
影响因子：
7.8
作者：
Gilley, Jonathan;Coffer, Paul J;Ham, Jonathan
通讯作者：
Ham, Jonathan
影响因子：
4.8
作者：
Guo, SD;Rena, G;Unterman, T
通讯作者：
Unterman, T
影响因子：
4.4
作者：
Anderson, MJ;Viars, CS;Arden, KC
通讯作者：
Arden, KC
影响因子：
11.4
作者：
Bois, PRJ;Grosveld, GC
通讯作者：
Grosveld, GC