Elsevier

Brain Research

Volume 835, Issue 1, 17 July 1999, Pages 10-17
Brain Research

Interactive report
ΔFosB: a molecular mediator of long-term neural and behavioral plasticity1

https://doi.org/10.1016/S0006-8993(98)01191-3Get rights and content

Abstract

ΔFosB, a member of the Fos family of transcription factors, is derived from the fosB gene via alternative splicing. Just as c-Fos and many other Fos family members are induced rapidly and transiently in specific brain regions in response to many types of acute perturbations, novel isoforms of ΔFosB accumulate in a region-specific manner in brain uniquely in response to many types of chronic perturbations, including repeated administration of drugs of abuse or of antidepressant or antipsychotic treatments. Importantly, once induced, these ΔFosB isoforms persist in brain for relatively long periods due to their extraordinary stability. Mice lacking the fosB gene show abnormal biochemical and behavioral responses to chronic administration of drugs of abuse or antidepressant treatments, consistent with an important role for ΔFosB in mediating long-term adaptations in the brain. More definitive evidence to support this hypothesis has recently been provided by inducible transgenic mice, wherein biochemical and behavioral changes, which mimic the chronic drug-treated state, are seen upon overexpression of ΔFosB in specific brain regions. This evolving work supports the view that ΔFosB functions as a type of `molecular switch' that gradually converts acute responses into relatively stable adaptations that underlie long-term neural and behavioral plasticity to repeated stimuli.

Introduction

The brain is remarkable for its ability to adapt and respond over time to repeated perturbations. Some of these adaptations are good, for example, those underlying learning and memory or the therapeutic responses to treatments for a host of neuropsychiatric disorders. Other adaptations (or maladaptations) are not good, for example, those underlying drug addiction or pathological responses to severe stress. Understanding the molecular basis of these adaptations and maladaptations is one of the greatest challenges of modern neuroscience.

Since many of these adaptations are relatively stable — that is, they persist for a long time (in some cases even a lifetime) after the perturbation ceases — it has been suggested that regulation of gene expression is one important underlying mechanism involved [20]. This has focused research on transcription factors, nuclear proteins that bind to specific sequences of DNA present within the regulatory regions of particular genes and thereby increase or decrease the rate at which those genes are transcribed. Although it is likely that post-transcriptional mechanisms are also important in mediating long-lasting adaptations in the brain, regulation of transcriptional mechanisms remain the best studied.

Of the numerous types of transcription factors known to exist in brain, the Fos-Jun families have received considerable attention. Heterodimers of Fos- and Jun-like proteins form the AP-1 (activator protein-1) transcription factor, which binds to specific AP-1 sites present within the regulatory regions of certain genes [27]. The genes encoding Fos and Jun family proteins have been termed immediate early genes, since they can be induced in brain very rapidly, and in a region-specific manner, in response to diverse types of stimuli, including electrical stimulation, physiological perturbations, stress, and psychotropic drugs 19, 27, 35. This induction is also transient, such that Fos and Jun family proteins return to basal levels within hours of the original stimulus. The net result is the rapid, but transient, formation of an AP-1 complex, which is thought to alter the expression of specific target genes in those brain regions and thereby mediate short-lived changes in gene expression. Although numerous neural genes are known to contain AP-1 sites, it has been difficult to establish any particular genes as physiological targets for AP-1 complexes in the brain in vivo.

In recent years, evidence has supported the existence of novel forms of Fos family proteins that do not follow this temporal pattern typical of other family members. These proteins, originally termed chronic FRAs (Fos-related antigens), were shown to be induced in specific brain regions uniquely after many types of chronic perturbations 17, 18, 31. Once induced, these proteins were also shown to be relatively stable in that they persisted in brain for weeks or months after the perturbation. These findings led to the hypothesis that the chronic FRAs, and the chronic AP-1 complex they formed, are unique mediators of long-term changes in gene expression in the brain. Recently, the chronic FRAs have been shown to be novel isoforms of ΔFosB, a product of the fosB gene. The goal of this review is to summarize our current knowledge of these ΔFosB isoforms and illustrate the utility of genetic mutant mice in delineating the important role played by this transcription factor in the long-term regulation of brain function.

Section snippets

Region-specific induction of chronic FRAs in brain by diverse types of chronic stimuli

The chronic FRAs were first identified as Fos-like proteins of 35–37 kD on western blots utilizing antisera directed against a moiety common to all known Fos family members. Over the past 5 years, these proteins have been shown to be induced after many types of chronic perturbations, as outlined in Table 1. Such stimuli include chronic administration of several types of drugs of abuse, such as cocaine, amphetamine, opiates, and nicotine (see Table 1 for refs). Repeated exposure to

Chronic FRAs are highly stable isoforms of ΔFosB

Although the chronic FRAs were shown to be immunochemically related to ΔFosB in early studies [18], it was thought that they were not ΔFosB per se for two reasons. First, the chronic FRAs (which migrate as multiple 35–37 kD bands on one and two dimensional gels) could be distinguished from ΔFosB, which migrates as a single 33 kD protein and is induced in brain, albeit to very low levels, by several acute stimuli 4, 18. Second, levels of ΔfosB mRNA were shown to be very low under conditions at

fosb knockout mice

The first evidence to support the hypothesis that ΔFosB plays an important role in mediating chronic adaptations in the brain has come from the study of mice lacking the fosB gene. In one study, fosB knockout mice were found to exhibit heightened sensitivity to the locomotor-activating and rewarding effects of cocaine (Fig. 2) [14]. This would suggest that ΔFosB could represent a mechanism of tolerance, such that its induction in striatum by chronic cocaine administration would serve to reduce

Tissue-specific, inducible transgenic mice that overexpress ΔFosB

To overcome these limitations with the fosB mutants, we have generated transgenic mice in which ΔFosB can be induced in specific brain regions of adult animals [6]. For this purpose, we used the tetracycline gene regulation system 10, 11, which involves two genes (Fig. 3). One gene encodes the tetracycline transactivator (tTA), a tetracycline-inhibitable transcription factor. The second gene encodes the protein of interest (e.g., ΔFosB) under the control of the TetOp promoter, which is

Conclusions

Increasing evidence supports the view that ΔFosB is an important mediator of long-term plasticity in the brain. One major challenge for future research is to identify the precise biochemical modification (presumably phosphorylation) which is responsible for stabilizing the chronic isoforms of ΔFosB. This knowledge could make it possible to intervene, by either mimicking or preventing this stabilization, which might eventually be exploited for a variety of medicinal purposes.

Another major

Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health and by the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center, State of Connecticut Department of Mental Health and Addiction Services.

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