Fig. 1. Scheme showing the gradual accumulation of ΔFosB versus the rapid and transient induction of other Fos family proteins. (Top graph) Several waves of Fos family proteins [comprised of c-Fos, FosB, ΔFosB (33-kDa isoform), Fra-1, Fra-2] are induced in a region-specific manner in brain by acute administration of any of several stimuli (see Table 1). Also induced are biochemically modified isoforms of ΔFosB (35–37 kDa); they, too, are induced (although at low levels) following an acute stimulus, but persist in brain for long periods due to their stability. (Bottom graph) With repeated (e.g., twice daily) stimulation, each acute stimulus induces a low level of the stable ΔFosB isoforms. This is indicated by the lower set of overlapping lines, which indicate ΔFosB induced by each acute stimulus. The result is a gradual increase in the total levels of ΔFosB with repeated stimuli during a course of chronic treatment. This is indicated by the increasing stepped line in the graph. The gel inset shows an example of this phenomenon: the induction of c-Fos, FosB, Fra-1/2, and the 33-kDa isoform of ΔFosB in the nucleus accumbens after an acute cocaine exposure, and the switch to the predominant and selective induction of 35–37 kDa isoforms of ΔFosB after chronic cocaine administration. From [38].

Fig. 2. Illustration of the tetracycline gene regulation system. One transgene expresses tTA under the control of a promoter of choice. The other transgene expresses the protein of interest under the control of the TetOp promoter, which is activated by tTA. Doxycycline (doxy; a tetracycline derivative) binds to tTA and prevents this action. In the example shown [31 and 17], a fragment of the neuron-specific enolase (NSE) promoter is used to drive tTA, and the TetOp-driven gene is ΔFosB. In bitransgenic mice, removal of doxy causes the induction of ΔFosB selectively in cells in which the NSE promoter is active.

Fig. 3. Regulation of gene expression by cocaine: comparison to effects of CREB and ΔFosB. Mice carrying the NSE-tTA transgene alone were given daily i.p. injections of cocaine (10 mg/kg) or saline for 5 days (A), or cocaine (15 mg/kg) or saline for 5 days/week×4 consecutive weeks (B), and were sacrificed 24 h after the last injection. RNA was isolated from the nucleus accumbens and subjected to microarray analysis. (A) Venn diagram showing the number of genes with shared up-regulation between short-term cocaine treatment and short-term ΔFosB (1–2 weeks), and CREB (8 weeks) expression. (B) Venn diagram showing the number of genes with shared up-regulation between long-term cocaine treatment and long-term ΔFosB (4–8 weeks) and CREB expression.

Table 1. Examples of stimuli that induce ΔFosB in brain after chronic exposure

Table 2. Behavioral phenotype upon ΔFosB induction in dynorphin+/substance P+ neurons of nucleus accumbens and dorsal striatuma

Table 3. Examples of bona fide target genes for ΔFosB in braina