Mania-like behavior induced by disruption of CLOCK

• DOI: 10.1073/pnas.0609625104
• Publication Date: 2007-03-23T00:18:44Z
• Authors: 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
• Keywords: Haploinsufficiency; PER2

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