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


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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    ABSTRACT: Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation,which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus–pituitary–adrenal (HPA) axis have close interactionswith pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.
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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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    ABSTRACT: The NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways, providing a mechanism for the cells in response to a wide variety of stimuli linking to inflammation. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-κB pathways. To initiate both of these pathways, IκB-degradation triggers NF-κB release and the nuclear translocated-heterodimer (or homodimer) can associate with the κB sites of promoter to regulate the gene transcriptions. NF-κB ubiquitously expresses in neurons and the constitutive NF-κB activation is associated with processing of neuronal information. NF-κB can regulate the transcription of genes such as chemokines, cytokines, proinflammatory enzymes, adhesion molecules, proinflammatory transcription factors, and other factors to modulate the neuronal survival. In neuronal insult, NF-κB constitutively active in neuron cell bodies can protect neurons against different injuries and regulate the neuronal inflammatory reactions. Besides neurons, NF-κB transcription factors are abundant in glial cells and cerebral blood vessels and the diverse functions of NF-κB also regulate the inflammatory reaction around the neuronal environment. NF-κB transcription factors are abundant in the brain and exhibit diverse functions. Several central nerve system (CNS) diseases are linked to NF-κB activated by inflammatory mediators. The RelA and c-Rel expression produce opposite effects on neuronal survival. Importantly, c-Rel expression in CNS plays a critical role in anti-apoptosis and reduces the age-related behaviors. Moreover, the different subunits of NF-κB dimer formation can modulate the neuroninflammation, neuronal protection, or neurotoxicity. The diverse functions of NF-κB depend on the subunits of the NF-κB dimer-formation which enable us to develop a therapeutic approach to neuroinflammation based on a new concept of inflammation as a strategic tool in neuronal cells. However, the detail role of NF-κB in neuroinflammation, remains to be clarified. In the present article, we provide an updated review of the current state of our knowledge about relationship between NF-κB and neuroinflammation.
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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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