title: Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice.
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.
authors: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294, USA.
authors: Wenjun
authors: W
authors: Zhou
authors: Ligong
authors: L
authors: Chen
authors: Sufen
authors: S
authors: Yang
authors: Fuzeng
authors: F
authors: Li
authors: Xiaohua
authors: X
authors: Li
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006380:Helplessness, Learned; D008297:Male; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3