Article

Nuclear factor- B is a critical mediator of stress-impaired neurogenesis and depressive behavior

Department of Psychiatry and Pharmacology, Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine, New Haven, CT 06519, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2010; 107(6):2669-74. DOI: 10.1073/pnas.0910658107
Source: PubMed

ABSTRACT

Proinflammatory cytokines, such as IL-1beta, have been implicated in the cellular and behavioral effects of stress and in mood disorders, although the downstream signaling pathways underlying these effects have not been determined. In the present study, we demonstrate a critical role for NF-kappaB signaling in the actions of IL-1beta and stress. Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-kappaB. Further analysis reveals that stress activates NF-kappaB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-kappaB signaling. Together, these data identify NF-kappaB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.

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    • "The activation of NF-κB is regulated by glucocorticoids that inhibit NF-κB activity, which in turn decrease the activation of pro-inflammatory cytokines (Padgett and Glaser, 2003). NF-κB is crucial for mediating stress-induced impaired neurogenesis and depression (Koo et al., 2010). A MAPK pathway is also important for the inhibitory action of proinflammatory cytokines. "
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    • "In the CNS, NF-κB transcription factors are key players in a number of physiological processes such as neurogenesis (Koo et al., 2010), neuritogenesis (Rolls et al., 2007), and synaptic plasticity which related to learning and memory (Levenson et al., 2004; O'Riordan et al., 2006; Ahn et al., 2008). A number of studies also provide evidence that activation of NF-κB protects neurons against the different injuries such as excitotoxicity (Mattson, 2005), and oxidative stress (Sarnico et al., 2009b), as well as amyloid β peptide toxicity (Barger et al., 1995; Kaltschmidt et al., 1997) and exerts as a cellular defense program. "
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    • "In rodents, olfactory bulbectomy (OBX) leads to numerous behavioural deficits, including cognitive deficits and anhedonia that are used to model major depression, but may also represent a valuable tool in the study of neurodegenerative disorders like AD [5] [6] [7]. Indeed, OBX has been reported to decrease hippocampal neurogenesis, a putative pathogenic mechanism in AD and depression [8] [9]. "
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