Mania-like behavior induced by disruption of CLOCK.
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.
Roybal
Kole
K
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Theobold
David
D
Graham
Ami
A
DiNieri
Jennifer A
JA
Russo
Scott J
SJ
Krishnan
Vaishnav
V
Chakravarty
Sumana
S
Peevey
Joseph
J
Oehrlein
Nathan
N
Birnbaum
Shari
S
Vitaterna
Martha H
MH
Orsulak
Paul
P
Takahashi
Joseph S
JS
Nestler
Eric J
EJ
Carlezon
William A
WA
McClung
Colleen A
CA
D000704:Analysis of Variance; D000818:Animals; D001526:Behavioral Symptoms / Q000235:genetics; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D018020:Lithium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics* / Q000627:therapeutic use; D017557:Ventral Tegmental Area / Q000187:drug effects
D018020:Lithium Compounds; D015534:Trans-Activators; D008094:Lithium; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3