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Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice.

ABSTRACT: 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.We tested the response of brain FoxO3a in the learned helplessness (LH) paradigm and tested signaling pathways that mediate the response of FoxO3a.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 (GSK3?). Noticeably, FoxO3a formed a protein complex with GSK3? 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 GSK3?-FoxO3a interaction, and reduce nuclear FoxO3a accumulation. In vitro approaches further revealed that the interaction between GSK3? and FoxO3a was strongest when both were active; FoxO3a was phosphorylated by recombinant GSK3?; 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.FoxO3a is activated in response to IES by interacting with GSK3?, and inhibition of GSK3? or reducing FoxO3a expression promotes resistance to stress-induced behavioral disturbance by disrupting this signaling mechanism.

SUBMITTER: Zhou W

PROVIDER: S-EPMC3254805 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice.

Zhou Wenjun W Chen Ligong L Yang Sufen S Li Fuzeng F Li Xiaohua X

Biological psychiatry 20111005 7

<h4>Background</h4>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.<h4>Methods</h4>We tested the response of brain FoxO3a in the learned helplessness (LH) paradigm and tested signaling pathways that mediate the response of FoxO3a.<h4>Results</h4>A single session of inescapable shocks (IES) in mice reduced FoxO3a phosphorylation at the Akt-regulating serine/threo ...[more]

PMID: 21978520

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Project description:Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence-a critical period of frontal lobe development-influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.

Dataset Information

Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice.

Publications

Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice.

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