Nuclear factor kB signaling regulates neuronal morphology and cocaine reward

Scott J. Russo, Matthew B. Wilkinson, Michelle S. Mazei-Robison, David M. Dietz, Ian Maze, Vaishnav Krishnan, William Renthal, Ami Graham, Shari G. Birnbaum, Thomas A. Green, Bruce Robison, Alan Lesselyong, Linda I. Perrotti, Carlos A. Bolaños, Arvind Kumar, Michael S. Clark, John F. Neumaier, Rachael L. Neve, Asha L. Bhakar, Philip A. Barker & 1 others Eric J. Nestler

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Abstract

Although chronic cocaine-induced changes in dendritic spines on nucleus accumbens (NAc) neurons have been correlated with behavioral sensitization, the molecular pathways governing these structural changes, and their resulting behavioral effects, are poorly understood. The transcription factor, nuclear factor κB (NFκB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFκB in regulating cocaine-induced dendritic spine changes on medium spiny neurons of the NAc and the rewarding effects of cocaine. We show that chronic cocaine induces NFκB-dependent transcription in the NAc of NFκB-Lac transgenic mice. This induction of NFκB activity is accompanied by increased expression of several NFNFκB genes, the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their transcriptional activation. To study the functional significance of this induction, we used viral-mediated gene transfer to express either a constitutively active or dominant-negative mutant of Inhibitor of κ B kinase (IKKca or IKKdn), which normally activates NFκB signaling, in the NAc. We found that activation of NFNFκB by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NFκB by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NFκB blocks the rewarding effects of cocaine and the ability of previous cocaine exposure to increase an animal's preference for cocaine. Together, these studies establish a direct role for NFκB pathways in the NAc to regulate structural and behavioral plasticity to cocaine.

Original languageEnglish (US)
Pages (from-to)3529-3537
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number11
DOIs
StatePublished - Mar 18 2009

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Reward
Cocaine
Nucleus Accumbens
Dendritic Spines
Neurons
Aptitude
Viral Genes
Transgenic Mice
Transcriptional Activation
Chromatin
Transcription Factors
Phosphotransferases
Gene Expression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Russo, S. J., Wilkinson, M. B., Mazei-Robison, M. S., Dietz, D. M., Maze, I., Krishnan, V., ... Nestler, E. J. (2009). Nuclear factor kB signaling regulates neuronal morphology and cocaine reward. Journal of Neuroscience, 29(11), 3529-3537. https://doi.org/10.1523/JNEUROSCI.6173-08.2009

Nuclear factor kB signaling regulates neuronal morphology and cocaine reward. / Russo, Scott J.; Wilkinson, Matthew B.; Mazei-Robison, Michelle S.; Dietz, David M.; Maze, Ian; Krishnan, Vaishnav; Renthal, William; Graham, Ami; Birnbaum, Shari G.; Green, Thomas A.; Robison, Bruce; Lesselyong, Alan; Perrotti, Linda I.; Bolaños, Carlos A.; Kumar, Arvind; Clark, Michael S.; Neumaier, John F.; Neve, Rachael L.; Bhakar, Asha L.; Barker, Philip A.; Nestler, Eric J.

In: Journal of Neuroscience, Vol. 29, No. 11, 18.03.2009, p. 3529-3537.

Research output: Contribution to journalArticle

Russo, SJ, Wilkinson, MB, Mazei-Robison, MS, Dietz, DM, Maze, I, Krishnan, V, Renthal, W, Graham, A, Birnbaum, SG, Green, TA, Robison, B, Lesselyong, A, Perrotti, LI, Bolaños, CA, Kumar, A, Clark, MS, Neumaier, JF, Neve, RL, Bhakar, AL, Barker, PA & Nestler, EJ 2009, 'Nuclear factor kB signaling regulates neuronal morphology and cocaine reward', Journal of Neuroscience, vol. 29, no. 11, pp. 3529-3537. https://doi.org/10.1523/JNEUROSCI.6173-08.2009
Russo SJ, Wilkinson MB, Mazei-Robison MS, Dietz DM, Maze I, Krishnan V et al. Nuclear factor kB signaling regulates neuronal morphology and cocaine reward. Journal of Neuroscience. 2009 Mar 18;29(11):3529-3537. https://doi.org/10.1523/JNEUROSCI.6173-08.2009
Russo, Scott J. ; Wilkinson, Matthew B. ; Mazei-Robison, Michelle S. ; Dietz, David M. ; Maze, Ian ; Krishnan, Vaishnav ; Renthal, William ; Graham, Ami ; Birnbaum, Shari G. ; Green, Thomas A. ; Robison, Bruce ; Lesselyong, Alan ; Perrotti, Linda I. ; Bolaños, Carlos A. ; Kumar, Arvind ; Clark, Michael S. ; Neumaier, John F. ; Neve, Rachael L. ; Bhakar, Asha L. ; Barker, Philip A. ; Nestler, Eric J. / Nuclear factor kB signaling regulates neuronal morphology and cocaine reward. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 11. pp. 3529-3537.
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AU - Krishnan, Vaishnav

AU - Renthal, William

AU - Graham, Ami

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AU - Green, Thomas A.

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AU - Bolaños, Carlos A.

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