Researchers Discover Anxiety And Aggression Gene In Mice; Opens New Door To Study Of Mood Disorders In Humans

(Videos displaying aggressive behavior of Pet-1 knockout mice can be viewed at http://neurowww.cwru.edu/faculty/deneris.shtml ; click Movies Link.)

Other neurologic functions, such as motor coordination, feeding, and locomotor activity, do not appear altered in the knockout mouse.

Anxiety and aggression are normal and important behaviors that allow individuals to respond appropriately to threats or cope with a challenging environment. However, it is clear that uncontrollable or excessive anxiety and aggression can be counterproductive.

"The behavior of Pet-1 knockout mice is strikingly reminiscent of some human psychiatric disorders that are characterized by heightened anxiety and violence," says Evan Deneris, Ph.D., principal investigator of the study and a neuroscientist at CWRU. The study is published in the Jan. 23 issue of the science journal Neuron.

Previously, Deneris' lab showed that in the brain Pet-1 is active only in serotonin nerve cells or neurons, a relatively small number of cells (among the trillions of neurons in a human brain, only a few hundred thousand produce serotonin) that profoundly affect emotions. Serotonin is a chemical that acts as a messenger or neurotransmitter allowing neurons to communicate with one another in the brain and spinal cord. It is important for ensuring an appropriate level of anxiety and aggression. Defective serotonin neurons have been linked to excessive anxiety, impulsive violence, and depression in humans.

Antidepressant drugs such as Prozac and Zoloft work by increasing serotonin activity and are highly effective at treating many of these disorders. But it is unknown why some people have dysfunctional serotonin neurons and whether this can be caused by defects in genes that are normally required for their early development.

"We have now shown that Pet-1 is required specifically for fetal development of serotonin neurons," says Deneris. In mice missing this gene, most serotonin neurons fail to be generated in the fetus and the ones that remain are defective. This leads to very low serotonin levels throughout the developing brain, which in turn results in altered behavior in adults. "This is the first gene shown to impact adult emotional behavior through specific control of fetal serotonin neuron development."

Deneris and his colleagues employed sensitive tests of aggression and anxiety to compare the behavior of the knockout mice to wild type mice. One such aggression test measures a mouse's response time to an intruder mouse entering its territory. The Pet-1 knockout mice attacked intruders much more quickly and more often than wild type mice. In fact, knockout mice often would not engage in normal exploratory behavior directed toward the intruder before attacking it. Excessive anxiety-like behavior was evident in another test, measuring the amount of time a mouse spends in open unprotected areas of a test chamber compared to closed protected areas. Unlike normal mice, which will enter and explore an unprotected portion of the test chamber, the Pet-1 knockout mice avoided this area all together, indicating abnormal anxiety-like behavior.

The human and mouse serotonin systems share many anatomical and functional features, and the same Pet-1 gene is present in the human genome. Therefore, Deneris' discovery creates the first animal model for gaining a greater understanding of the causes of abnormal anxiety and aggression brought about through defective early serotonin neuron development. Deneris also sees this knockout mouse being used as a model for screening new drugs that can treat both aggression and anxiety. "If in fact particular genetic variants of Pet-1 are associated with excessive anxiety or violent activity in humans, then tests to detect these variants might be useful for early diagnosis of people who may be at risk for developing these abnormal behaviors," Deneris says. His lab plans more studies in mice to see how the gene affects sleep-wake patterns, learning and memory, and sexual behavior – all functions controlled in part by serotonin.

Lead authors on the study are Timothy J. Hendricks, and Dmitry V. Fyodorov, who were graduate students in Deneris's lab at the time of the study. Other authors are, from CWRU: Lauren J. Wegman, Nadia B. Lelutiu, Elizabeth A. Pehek, Ph.D., Bryan Yamamoto, Ph.D., and Jerry Silver, Ph.D.; and, from Baylor College of Medicine, Edwin J. Weeber, Ph.D., and J. David Sweatt, Ph.D.