Abstract：
BACKGROUND:The transcription factor FoxO3a is highly expressed in brain, but little is known about the response of FoxO3a to behavioral stress and its impact in the associated behavioral changes. METHODS:We tested the response of brain FoxO3a in the learned helplessness (LH) paradigm and tested signaling pathways that mediate the response of FoxO3a. RESULTS:A single session of inescapable shocks (IES) in mice reduced FoxO3a phosphorylation at the Akt-regulating serine/threonine residues and induced prolonged nuclear accumulation of FoxO3a in the cerebral cortex, both indicating activation of FoxO3a in brain. The response of FoxO3a is accompanied by a transient inactivation of Akt and a prolonged activation of glycogen synthase kinase-3beta (GSK3β). Noticeably, FoxO3a formed a protein complex with GSK3β in the cerebral cortex, and the interaction between the two proteins was stronger in IES-treated mice. Inhibition of glycogen synthase kinase-3 was able to abolish IES-induced LH behavior, disrupt IES-induced GSK3β-FoxO3a interaction, and reduce nuclear FoxO3a accumulation. In vitro approaches further revealed that the interaction between GSK3β and FoxO3a was strongest when both were active; FoxO3a was phosphorylated by recombinant GSK3β; and glycogen synthase kinase-3 inhibitors effectively reduced FoxO3a transcriptional activity. Importantly, IES-induced LH behavior was markedly diminished in FoxO3a-deficient mice that had minimal FoxO3a expression and reduced levels of FoxO3a-inducible genes. CONCLUSIONS:FoxO3a is activated in response to IES by interacting with GSK3β, and inhibition of GSK3β or reducing FoxO3a expression promotes resistance to stress-induced behavioral disturbance by disrupting this signaling mechanism.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Zhou W,Chen L,Yang S,Li F,Li Xdoi
10.1016/j.biopsych.2011.08.012subject
Has Abstractpub_date
2012-04-01 00:00:00pages
583-92issue
7eissn
0006-3223issn
1873-2402pii
S0006-3223(11)00818-3journal_volume
71pub_type
杂志文章abstract：:Long-term normal-dose benzodiazepine treatment in seven patients was associated with reduced urinary excretion of MOPEG (4-hydroxy-3-methoxy-phenylglycol). Following the discontinuation of the drugs a characteristic withdrawal reaction occurred, with an increase towards normal values of the MOPEG excretion levels and ...
journal_title：Biological psychiatry
pub_type： 杂志文章
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更新日期：1983-02-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Biological psychiatry
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journal_title：Biological psychiatry
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journal_title：Biological psychiatry
pub_type： 杂志文章
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：
更新日期：1983-06-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
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更新日期：2007-01-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
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journal_title：Biological psychiatry
pub_type： 杂志文章,评审
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journal_title：Biological psychiatry
pub_type： 杂志文章
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：10.1016/j.biopsych.2005.04.016
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章
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更新日期：1989-07-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章,多中心研究,随机对照试验
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：
更新日期：1981-12-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章
doi：10.1016/j.biopsych.2006.08.018
更新日期：2007-04-15 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
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更新日期：2000-01-15 00:00:00
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
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更新日期：2002-09-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：10.1016/j.biopsych.2007.04.039
更新日期：2007-11-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：10.1016/j.biopsych.2010.07.033
更新日期：2010-12-01 00:00:00
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：10.1016/s0006-3223(99)00109-2
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journal_title：Biological psychiatry
pub_type： 杂志文章
doi：10.1016/j.biopsych.2004.01.024
更新日期：2004-05-15 00:00:00
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journal_title：Biological psychiatry
pub_type： 临床试验,杂志文章
doi：10.1016/j.biopsych.2004.06.031
更新日期：2004-10-01 00:00:00
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pub_type： 杂志文章,评审
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更新日期：2003-05-01 00:00:00
