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Faulty body clock may cause mania
Mice with a gene mutation that disrupts their sleep cycles show signs of hyperactivity and addictive tendencies, a new study reveals.
Researchers say that such "manic" behaviour displayed by the animals bolsters the theory that glitches in the body's internal clock can cause psychiatric illnesses such as bipolar disorder.
Mice that received injections of DNA to compensate for the mutated gene regained regular sleep cycles and showed normal behaviour. This type of gene therapy will not work to treat people with bipolar disorder anytime soon, researchers stress, but they believe genetic experiments in rodents will reveal the potential targets for psychiatric drug treatments.
Colleen McClung at the University of Texas Southwestern Medical Center in Dallas, US, and colleagues conducted experiments on mice with a mutation in their Clock gene. This gene normally activates other genes in the cell – with a certain regularity and on a daily basis. The human version is thought to be responsible for many of our circadian rhythms, including our wake/sleep cycle.
Previous mouse studies have shown that a faulty version of Clock disrupts biological rhythms, leading to irregular sleep.
Easily addicted
McClung's team tested the mice to see whether they showed hyperactivity and addictive tendencies – two behaviours associated with mania in people. Researchers placed the animals in cages designed to sense movement. The mice with the Clock mutation showed far greater physical activity than their control counterparts.
A separate part of the experiment demonstrated that the experimental mice showed a greater tendency towards cocaine addiction: mice with the flawed Clock gene self-administered the drug more frequently than those without the genetic mutation. The "mutant" mice also displayed more boldness by exploring unsheltered areas of cages and mazes.
"These behaviours correlate with the sense of euphoria and mania that bipolar patients experience," says McClung.
She notes that lithium – a drug commonly used to treat bipolar disorder – restored normal behaviour in the mutant mice. McClung's team also tried a novel approach that involved injecting normal copies of the Clock gene into the brains of the mice during early adulthood. Animals that received these injections did not show signs of hyperactivity or extreme boldness.
McClung does not advocate using a similar gene therapy approach in humans any time soon: "It's way too early to say that would work – especially because these mice are only showing the manic side of bipolar disorder."
Pleasure signals
Exactly how the mutations in the Clock gene lead to hyperactivity and extreme boldness remains unknown. However, some experiments have suggested that the protein made by the gene activates genes involved in the production of dopamine, the reward-signalling molecule.
Since humans have an analogous version of the Clock gene, McClung speculates that glitches in the body's daily clock could disrupt pleasure signalling in the brain, leading to the mania and depression that characterise bipolar disorder.
She notes that gene surveys have linked Clock mutations with bipolar disorder in people (American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol 123, p 23).
David Fleck at the University of Cincinnati, Ohio, US, says that irregular sleep patters "are one of the most frequent symptoms" of this mental illness. He adds that the results from the McClung's experiment should encourage drug-makers to consider designing medications that target the Clock gene pathway.
Mice with a gene mutation that disrupts their sleep cycles show signs of hyperactivity and addictive tendencies, a new study reveals.
Researchers say that such "manic" behaviour displayed by the animals bolsters the theory that glitches in the body's internal clock can cause psychiatric illnesses such as bipolar disorder.
Mice that received injections of DNA to compensate for the mutated gene regained regular sleep cycles and showed normal behaviour. This type of gene therapy will not work to treat people with bipolar disorder anytime soon, researchers stress, but they believe genetic experiments in rodents will reveal the potential targets for psychiatric drug treatments.
Colleen McClung at the University of Texas Southwestern Medical Center in Dallas, US, and colleagues conducted experiments on mice with a mutation in their Clock gene. This gene normally activates other genes in the cell – with a certain regularity and on a daily basis. The human version is thought to be responsible for many of our circadian rhythms, including our wake/sleep cycle.
Previous mouse studies have shown that a faulty version of Clock disrupts biological rhythms, leading to irregular sleep.
Easily addicted
McClung's team tested the mice to see whether they showed hyperactivity and addictive tendencies – two behaviours associated with mania in people. Researchers placed the animals in cages designed to sense movement. The mice with the Clock mutation showed far greater physical activity than their control counterparts.
A separate part of the experiment demonstrated that the experimental mice showed a greater tendency towards cocaine addiction: mice with the flawed Clock gene self-administered the drug more frequently than those without the genetic mutation. The "mutant" mice also displayed more boldness by exploring unsheltered areas of cages and mazes.
"These behaviours correlate with the sense of euphoria and mania that bipolar patients experience," says McClung.
She notes that lithium – a drug commonly used to treat bipolar disorder – restored normal behaviour in the mutant mice. McClung's team also tried a novel approach that involved injecting normal copies of the Clock gene into the brains of the mice during early adulthood. Animals that received these injections did not show signs of hyperactivity or extreme boldness.
McClung does not advocate using a similar gene therapy approach in humans any time soon: "It's way too early to say that would work – especially because these mice are only showing the manic side of bipolar disorder."
Pleasure signals
Exactly how the mutations in the Clock gene lead to hyperactivity and extreme boldness remains unknown. However, some experiments have suggested that the protein made by the gene activates genes involved in the production of dopamine, the reward-signalling molecule.
Since humans have an analogous version of the Clock gene, McClung speculates that glitches in the body's daily clock could disrupt pleasure signalling in the brain, leading to the mania and depression that characterise bipolar disorder.
She notes that gene surveys have linked Clock mutations with bipolar disorder in people (American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol 123, p 23).
David Fleck at the University of Cincinnati, Ohio, US, says that irregular sleep patters "are one of the most frequent symptoms" of this mental illness. He adds that the results from the McClung's experiment should encourage drug-makers to consider designing medications that target the Clock gene pathway.