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The Journal of Neuroscience, November 24, 2004, 24(47):10594-10602; doi:10.1523/JNEUROSCI.2542-04.2004

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Behavioral/Systems/Cognitive
Induction of {Delta}FosB in Reward-Related Brain Structures after Chronic Stress

Linda I. Perrotti,1 Yuki Hadeishi,2 Paula G. Ulery,1 Michel Barrot,1 Lisa Monteggia,1 Ronald S. Duman,2 and Eric J. Nestler1

1Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, and 2Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508

Acute and chronic stress differentially regulate immediate-early gene (IEG) expression in the brain. Although acute stress induces c-Fos and FosB, repeated exposure to stress desensitizes the c-Fos response, but FosB-like immunoreactivity remains high. Several other treatments differentially regulate IEG expression in a similar manner after acute versus chronic exposure. The form of FosB that persists after these chronic treatments has been identified as {Delta}FosB, a splice variant of the fosB gene. This study was designed to determine whether the FosB form induced after chronic stress is also {Delta}FosB and to map the brain regions and identify the cell populations that exhibit this effect. Western blotting, using an antibody that recognizes all Fos family members, revealed that acute restraint stress caused robust induction of c-Fos and full-length FosB, as well as a small induction of {Delta}FosB, in the frontal cortex (fCTX) and nucleus accumbens (NAc). The induction of c-Fos (and to some extent full-length FosB) was desensitized after 10 d of restraint stress, at which point levels of {Delta}FosB were high. A similar pattern was observed after chronic unpredictable stress. By use of immunohistochemistry, we found that chronic restraint stress induced {Delta}FosB expression predominantly in the fCTX, NAc, and basolateral amygdala, with lower levels of induction seen elsewhere. These findings establish that chronic stress induces {Delta}FosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress on the brain.

Key words: c-Fos; stress; nucleus accumbens; prefrontal cortex; amygdala; reward

Received Oct 28, 2003; revised September 14, 2004; accepted September 14, 2004.




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