Mania-like behavior induced by disruption of CLOCK
| Autor: | Martha Hotz Vitaterna, Sumana Chakravarty, Jennifer A. DiNieri, Eric J. Nestler, Vaishnav Krishnan, Kole T. Roybal, Nathan Oehrlein, Joseph S. Takahashi, David Theobold, Ami Graham, Shari G. Birnbaum, Colleen A. McClung, William A. Carlezon, Scott J. Russo, Paul Orsulak, Joseph Peevey |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Bipolar Disorder medicine.drug_class CLOCK Proteins Behavioral Symptoms Lithium Biology Glycogen Synthase Kinase 3 Mice Internal medicine medicine Animals Circadian rhythm Bipolar disorder Medial forebrain bundle Analysis of Variance Multidisciplinary Glycogen Synthase Kinase 3 beta Ventral Tegmental Area Gene Transfer Techniques Mood stabilizer Genetic Therapy Biological Sciences medicine.disease Immunohistochemistry Electric Stimulation Circadian Rhythm CLOCK Ventral tegmental area medicine.anatomical_structure Endocrinology Gene Expression Regulation Mutagenesis Mutation Lithium Compounds Commentary Trans-Activators medicine.symptom Mania Locomotion |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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