Gene Knockout Unleashes Manic Mouse

April 5, 2007 • Science Update

Mice engineered to lack a specific gene showed behaviors similar to human mania in a study funded in part by NIMH; they were hyperactive, slept less, appeared less depressed and anxious, and craved sugar, cocaine and pleasure stimulation. The rodents’ behavior was more normal after lithium treatment or restoration of a functioning CLOCK protein, which the knocked-out gene codes for.

Drs. Colleen McClung and Eric Nestler, University of Texas, and colleagues, report on mouse model of human mania in the March 23, 2007 online edition of the Proceedings of the National Academy of Sciences.

Similar to the mice, people in the manic phase of bipolar disorder experience disruption of daily rhythms — sleep, appetite, activity — known to be regulated in part by the CLOCK protein. There is evidence that certain versions of the CLOCK gene may predispose for such circadian rhythm abnormalities in the disorder. People with mania also tend to engage in risky reward-seeking behavior.

To create the new mouse model, the researchers first molecularly engineered a strain of mice that lacked the CLOCK gene. The mutant rodents seemed wired for reward-seeking. They required lower-than-normal levels of electricity when their brain reward circuitry was directly stimulated, showed heightened reward-related and performance-enhancing effects with cocaine, and gorged on sugar.

Similar to manic patients, the mutant mice seemed relatively anxiety-free. They ventured where mice normally fear to tread — lingering in an unprotected open environment 13-times longer than usual. They were also undaunted by stressful situations that typically trigger depression-like reactions.

The mutant mice showed increased activity of the brain chemical messenger dopamine in the ventral tegmental area (VTA), hub of a key brain reward circuit. As with bipolar disorder patients, lithium treatment, known to reduce dopamine in this area, restored the aberrant mouse behaviors to normal.

In a clincher experiment, the researchers then used a modified virus to deliver a functional CLOCK protein to the VTA of mutant mice. This similarly led to more normal behavior, suggesting that CLOCK in the VTA may be a key player in mania.

The new mouse model holds promise for understanding CLOCK’s workings in mania not only in reward circuitry, but also in pathways that regulate circadian rhythms, where most previous research in this area had focused, note the researchers.

Reference

Roybal K, Theobold D, Graham A, Dinieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon WA Jr, McClung CA. Mania-like behavior induced by disruption of CLOCK . Proc Natl Acad Sci U S A. 2007 Mar 22; [Epub ahead of print] PMID: 17379666