Elsevier

Molecular Brain Research

Volume 132, Issue 2, 20 December 2004, Pages 146-154
Molecular Brain Research

Research report
ΔFosB: a molecular switch for long-term adaptation in the brain

https://doi.org/10.1016/j.molbrainres.2004.05.014Get rights and content

Abstract

ΔFosB is a unique transcription factor that plays an essential role in long-term adaptive changes in the brain associated with diverse conditions, such as drug addiction, Parkinson's disease, depression, and antidepressant treatment. It is induced in brain, in a region- and cell-type-specific manner by many types of chronic perturbations. Once induced, it persists for long periods of time due to its unusual stability. The transcriptional effects of ΔFosB are complex, because the protein can function as both a transcriptional activator and repressor. Progress has been made in identifying specific target genes for ΔFosB and in relating some of these genes to ΔFosB's cellular and behavioral actions. Future studies will help us to better understand the biochemical basis of ΔFosB's unique stability, as well as the precise molecular pathways through which this transcription factor produces its complex effects on neuronal plasticity and complex behavior.

Section snippets

Biochemical properties of ΔFosB

The Fos–Jun family of proteins forms the activator protein-1 (AP-1) transcription factor complex that binds AP-1 sites (consensus sequence: TGAC/GTCA) in gene promoters [36]. Genes encoding Fos and Jun family proteins are termed immediate early genes, because they are induced very rapidly in response to a variety of stimuli. This expression is transient, with mRNA and protein levels returning to normal within a few hours.

About 10 years ago, a broad band of Fos-like proteins, originally termed

Induction of ΔFosB in the nervous system

Several types of chronic perturbation have been shown to induce the 35- to 37-kDa isoforms of ΔFosB in the brain, with each type of stimulus showing region-specific patterns of induction (Table 1). Virtually all drugs of abuse induce ΔFosB, including cocaine, opiates, and nicotine, among others [30], [35], [40], [41], [46]. This induction is seen predominantly in the nucleus accumbens and dorsal striatum, although lower levels of induction are seen in several other brain areas, such as

Behavioral plasticity mediated by ΔFosB: role in drug addiction

The first direct evidence for the influence of ΔFosB on complex behavior was obtained from the study of FosB knockout mice [25]. We observed that FosB mutants display a heightened sensitivity to the initial locomotor and rewarding effects of cocaine. However, the mice fail to show behavioral sensitization that normally occurs with repeated drug administration. As well, the FosB mutants show abnormal biochemical, electrophysiological, and behavioral responses to electroconvulsive seizures ([26];

Behavioral plasticity mediated by ΔFosB: role in stress responses

Recent studies have begun to assess the role of ΔFosB in stress responses. While stress induces ΔFosB in several brain regions [45], its induction in nucleus accumbens and dorsal striatum can be best understood within a functional context. Thus, in light of the ability of ΔFosB in striatum to promote aspects of drug addiction, induction of the protein in this region by chronic stress may serve as one mechanism by which stress increases risk for addiction, as seen in many animal models as well

Behavioral plasticity mediated by ΔFosB: role in dyskinesia

Among the stimuli that robustly induce ΔFosB in striatal regions are first-generation antipsychotic drugs, as well as dopamine denervation coupled with repeated dopamine agonist treatment. Induction by chronic administration of antipsychotic drugs is mediated via the D2 antagonist properties of these agents [6], [24], [41]. Induction after dopamine denervation is presumably due to the supersensitivity of dopamine receptors that occurs under these conditions [22]. The functional consequences of

Genomic effects of ΔFosB: overall patterns of gene expression

Because ΔFosB is a transcription factor, it is likely that it produces these complex behavioral phenotypes to drugs of abuse and other stimuli by enhancing or repressing gene expression. As mentioned previously, ΔFosB is a truncated form of FosB that lacks most of the C-terminal transactivation domain of FosB but retains the dimerization and DNA-binding domains. ΔFosB is able to bind to all Jun family members in vitro and binds AP-1 sites in DNA. Although ΔFosB dimerizes predominantly with JunD

Genomic effects of ΔFosB: identification of candidate target genes

Several target genes of ΔFosB have been established using a candidate gene approach (Table 3). One candidate gene is GluR2, an AMPA glutamate receptor subunit [32]. ΔFosB overexpression in inducible bitransgenic mice selectively increases GluR2 expression in the nucleus accumbens, with no effect seen on several other AMPA glutamate receptor subunits analyzed. Conversely, expression of ΔcJun, a dominant negative inhibitor of AP-1 transcription, blocks the ability of cocaine to up-regulate GluR2

Genomic effects of ΔFosB: open-ended search for novel target genes

The second approach that has been used to identify target genes of ΔFosB has measured the gene expression changes that occur upon ΔFosB (or ΔcJun) expression using DNA microarrays, as described earlier. Studies using the bitransgenic mice that overexpress ΔFosB specifically in the striatum after doxycycline removal have led to the identification of many genes that are up- or down-regulated by ΔFosB expression [4], [18], [19], [34]. Two genes which appear to be induced through ΔFosB's actions as

Future directions

Increasing evidence supports the view that ΔFosB is a unique transcription factor based on its induction in brain by a range of chronic perturbations and on its high level of stability. There is also growing evidence for an important role of ΔFosB in animal models of drug addiction, Parkinson's disease, and depression and antidepressant action. Using both candidate gene and open-ended DNA microarray approaches, numerous putative targets for ΔFosB have been identified in brain, and in some cases

Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse and National Institute of Mental Health.

References (56)

  • M. Andersson et al.

    cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum

    J. Neurosci

    (2001)
  • M. Andersson et al.

    Time course of deltaFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment

    Eur. J. Neurosci

    (2003)
  • E. Ang et al.

    Induction of NFκB in nucleus accumbens by chronic cocaine administration

    J. Neurochem

    (2001)
  • J. Atkins et al.

    Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs

    Synapse

    (1999)
  • M. Barrot et al.

    CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

    Proc. Natl. Acad. Sci. U. S. A

    (2002)
  • O. Berton et al.

    ΔFosB in the dorsal raphe mediates stress-induced transcriptional changes in substance P neurons, and modulates behavioral profiles in the learned helplessness model of depression

    Abstr.-Soc. Neurosci

    (2003)
  • J.A. Bibb et al.

    Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5

    Nature

    (2001)
  • G. Bing et al.

    Long-term expression of Fos-related antigen and transient expression of delta FosB associated with seizures in the rat hippocampus and striatum

    J. Neurochem

    (1997)
  • T. Carle et al.

    Absence of conserved Fos family C-terminal domain in ΔFosB may contribute to its unique stability

    Abstr.-Soc. Neurosci

    (2003)
  • W.A. Carlezon et al.

    Regulation of cocaine reward by CREB

    Science

    (1998)
  • M.A. Cenci

    Transcription factors involved in the pathogenesis of l-DOPA-induced dyskinesia in a rat model of Parkinson's disease

    Amino Acids

    (2002)
  • J.S. Chen et al.

    Regulation of ΔFosB and FosB-like proteins by electroconvulsive seizure (ECS) and cocaine treatments

    Mol. Pharmacol

    (1995)
  • J. Chen et al.

    Chronic FRAs: stable variants of ΔFosB induced in brain by chronic treatments

    J. Neurosci

    (1997)
  • J.S. Chen et al.

    Transgenic animals with inducible, targeted gene expression in brain

    Mol. Pharmacol

    (1998)
  • J.S. Chen et al.

    Induction of cyclin-dependent kinase 5 in hippocampus by chronic electroconvulsive seizures: role of ΔFosB

    J. Neurosci

    (2000)
  • J. Chen et al.

    Downregulation of the CCAAT-enhancer binding protein beta in deltaFosB transgenic mice and by electroconvulsive seizures

    Neuropharmacology

    (2003)
  • C.R. Colby et al.

    ΔFosB enhances incentive for cocaine

    J. Neurosci

    (2003)
  • P. Dobrazanski et al.

    Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts

    Mol. Cell. Biol

    (1991)
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