Mania-like behavior induced by disruption of CLOCK

被引:583
作者
Roybal, Kole
Theobold, David
Graham, Ami
DiNieri, Jennifer A.
Russo, Scott J.
Krishnan, Vaishnav
Chakravarty, Sumana
Peevey, Joseph
Oehrlein, Nathan
Birnbaum, Shari
Vitaterna, Martha H.
Orsulak, Paul
Takahashi, Joseph S.
Nestler, Eric J.
Carlezon, William A., Jr.
McClung, Colleen A.
机构
[1] Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA
[3] Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat,Behav Genet Lab, Belmont, MA 02478 USA
[4] Vet Affairs N Texas Hlth Care Syst, Pathol & Lab Med Serv, Dallas, TX 75216 USA
[5] Northwestern Univ, Ctr Funct Genom, Evanston, IL 60208 USA
[6] Northwestern Univ, Dept Neurobiol & Physiol, Evanston, IL 60208 USA
[7] Northwestern Univ, Howard Hughes Med Inst, Dept Neurobiol & Physiol, Evanston, IL 60208 USA
关键词
bipolar disorder; circadian rhythms; dopamine;
D O I
10.1073/pnas.0609625104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 media[ 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.
引用
收藏
页码:6406 / 6411
页数:6
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