Delta FosB regulates wheel running - PubMed (original) (raw)

Delta FosB regulates wheel running

Martin Werme et al. J Neurosci. 2002.

Abstract

DeltaFosB is a transcription factor that accumulates in a region-specific manner in the brain after chronic perturbations. For example, repeated administration of drugs of abuse increases levels of DeltaFosB in the striatum. In the present study, we analyzed the effect of spontaneous wheel running, as a model for a natural rewarding behavior, on levels of DeltaFosB in striatal regions. Moreover, mice that inducibly overexpress DeltaFosB in specific subpopulations of striatal neurons were used to study the possible role of DeltaFosB on running behavior. Lewis rats given ad libitum access to running wheels for 30 d covered what would correspond to approximately 10 km/d and showed increased levels of DeltaFosB in the nucleus accumbens compared with rats exposed to locked running wheels. Mice that overexpress DeltaFosB selectively in striatal dynorphin-containing neurons increased their daily running compared with control littermates, whereas mice that overexpress DeltaFosB predominantly in striatal enkephalin-containing neurons ran considerably less than controls. Data from the present study demonstrate that like drugs of abuse, voluntary running increases levels of DeltaFosB in brain reward pathways. Furthermore, overexpression of DeltaFosB in a distinct striatal output neuronal population increases running behavior. Because previous work has shown that DeltaFosB overexpression within this same neuronal population increases the rewarding properties of drugs of abuse, results of the present study suggest that DeltaFosB may play a key role in controlling both natural and drug-induced reward.

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Figures

Fig. 1.

Regulation of Δ_FosB_ by wheel running. Levels of the 35–37 kDa isoforms of Δ_FosB_ were measured in the nucleus accumbens using Western blotting in control rats (C) and in rats that underwent 4 weeks of voluntary wheel running (R). Top, Representative lanes from the blots. Data are expressed as mean ± SEM (both groups, n = 7). *p < 0.05.

Fig. 2.

Wheel running affects the number of Δ_FosB_-positive cells in the nucleus accumbens.Top, Representative photomicrographs of rat brain sections demonstrating the increase in the number of Δ_FosB_-positive cells in the nucleus accumbens core when runners (Run) were compared with controls (Ctr). aca, Anterior commissure anterior.Bottom, Bar graph of counts of cells positive for Δ_FosB_-IR in the medial aspects of the core and shell of the nucleus accumbens in control rats and in rats that underwent 4 weeks of voluntary wheel running. Data are expressed as mean ± SEM (both groups, n = 8). *p < 0.05.

Fig. 3.

Cellular specificity of Δ_FosB_induction by wheel running. Representative photomicrographs of rat brain sections from eight individuals demonstrating colocalization of Δ_FosB_-IR (brown stained nuclei) and dynorphin mRNA (black grains) (a) or Δ_FosB_-IR and enkephalin mRNA in the nucleus accumbens core (b).

Fig. 4.

Expression of Δ_FosB_ in 11B mice. Brain sections were analyzed for Δ_FosB_-IR (brown-stained nuclei) followed by in situ hybridization for dynorphin mRNA (A) or enkephalin mRNA (B) (black grains). Note the preferential expression of Δ_FosB_-IR in the enkephalin-positive but not the dynorphin-positive cells. Of 214 Δ_FosB_-positive cells counted in three 11B mice, 73 ± 11% were also enkephalin positive, and 22 ± 6% were also dynorphin positive. No double-labeling was seen between Δ_FosB_ and interneuron markers.

Fig. 5.

Effect of Δ_FosB_ overexpression on wheel running behavior in bitransgenic mice. A, Bitransgenic mice drinking tap water have inducible overexpression of Δ_FosB_ in striatal dynorphin neurons (water) and showed increased running (distance per day) for the first 3 weeks of access to running wheels. In contrast, genetically identical littermate controls with doxycycline in their drinking water that do not overexpress Δ_FosB_ (dox) showed increased running for the first 2 weeks only. B, Another line of the bitransgenic strain of mice, called 11B, with inducible overexpression of Δ_FosB_ primarily in striatal enkephalin neurons (water) showed dramatically less running during their weeks 2 and 3 compared with genetically identical littermates that do not overexpress Δ_FosB_ (dox). # indicates an increase in running (distance per week) within a group. * indicates a difference in running between the Δ_FosB_overexpressers (water) and controls (dox). Vertical lines indicate borders between weeks 1 and 2, as well as weeks 2 and 3. Horizontal lines with the # symbol describe statistical differences between weekly running within a group. Data are expressed as mean (11A dox,n = 8; 11A water, n = 7; 11B dox, n = 6; 11B water, n = 7).#p < 0.05;##p < 0.01;###p < 0.001; *p< 0.05.

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Delta FosB regulates wheel running - PubMed (original) (raw)