Mania-like behavior induced by disruption of CLOCK

Kole Roybal, David Theobold, Ami Graham, Jennifer A. DiNieri, Scott J. Russo, Vaishnav Krishnan, Sumana Chakravarty, Joseph Peevey, Nathan Oehrlein, Shari Birnbaum, Martha H. Vitaterna, Paul Orsulak, Joseph S. Takahashi, Eric J. Nestler, William A. Carlezon, Colleen A. McClung

Research output: Contribution to journalArticle

561 Scopus citations

Abstract

Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.

Original languageEnglish (US)
Pages (from-to)6406-6411
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number15
DOIs
StatePublished - Apr 10 2007

Keywords

  • Bipolar disorder
  • Circadian rhythms
  • Dopamine

ASJC Scopus subject areas

  • General

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    Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., Vitaterna, M. H., Orsulak, P., Takahashi, J. S., Nestler, E. J., Carlezon, W. A., & McClung, C. A. (2007). Mania-like behavior induced by disruption of CLOCK. Proceedings of the National Academy of Sciences of the United States of America, 104(15), 6406-6411. https://doi.org/10.1073/pnas.0609625104