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Because circadian disruptions occur in mania, these researchers studied how genes that affect circadian pathways influence mania states. To do so, they compared behaviors consistent with human mania in wild-type mice and in mice engineered to have a mutant circadian gene (Clock) that expresses a protein that cannot activate transcription.
Compared with wild-type mice, mutant mice had lower voltage thresholds for, and increased rates of, a self-satisfying behavior (self-stimulation of the medial forebrain bundle via electrodes); greater preference for cocaine and sucrose; and in adverse situations, fewer anxiety-like and depression-like behaviors and a shorter latency to seeking a cracker. Administering lithium was associated with normative behaviors in the mutant mice. When the researchers inserted the wild-type gene directly into dopaminergic neurons in the ventral tegmental area (VTA), CLOCK expression normalized within the VTA, and the mutant mice displayed behaviors that were similar to those of wild-type mice.
Roybal K et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 2007 Apr 10; 104:6406-11.
Coyle JT. What can a clock mutation in mice tell us about bipolar disorder? Proc Natl Acad Sci U S A 2007 Apr 10; 104:6097-8.
Comment
A commentator notes that these results are consistent with several association studies of human circadian genetic polymorphisms, with the clinical effects of lithium, and with the mechanism of neuroleptics in the treatment of mania (they act on dopaminergic pathways, which include the VTA). However, these mutant mice did not display the cycling seen in human bipolar disorder. Other researchers have recently created a Clock-knockout mouse, which may allow study of mood switching.