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Receptor Knockout Yields an Adventurous Mouse

Press Release

Mice altered to lack a particular type of receptor in the brain's executive hub are more prone to go where normal mice fear to tread, NIMH funded scientists have discovered. In choosing between the dueling impulses to seek novelty vs. avoid a threat, whether an animal tended to venture out or to play-it-safe hinged on the presence of serotonin 2A receptors in the brain's outer layer, or cortex. Drs. Jay Gingrich, Rene Hen, Noelia Weisstaub, and colleagues at Columbia University, molecularly knocked out the gene that codes for the receptor in the cortex to pinpoint the neural underpinnings of such approach-avoidance conflict anxiety. They report on their findings in the July 28 issue of Science.

While it was known that serotonin plays a key role in mediating such anxiety-related behavior, how and where this happens in the brain has been unclear.

To find out, the researchers first molecularly engineered a strain of mice totally lacking the serotonin 2A receptor and put them in situations that pitted urges to seek new experiences against safety instincts. While normal mice tended to shun well-lit and open spaces as too risky, the knockout mice were more apt to explore such areas and quicker to begin eating in unfamiliar environments. Yet, when the researchers selectively restored the serotonin 2A receptors only to the brain's cortex, the knockout animals behaved just as anxiously as normal mice — confirming that the cortex is the seat of conflict anxiety.

When the knockout mice were put in situations involving inescapable stress, a model of depression, or conditioned fear, they behaved just like normal animals. This showed that the receptor's role appears to be specific for conflict anxiety.

The findings confirm that the receptors in the brain's thinking hub, as opposed to other areas where they exist, are critical for assessing risks. They also suggest that anti-anxiety drugs work by chronically blocking and causing a reduction in the gene expression for the 2A receptors, a process that typically takes a few weeks. The new insights into the workings of this system may lead to improved treatments for anxiety disorders, say the researchers.

Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzalez-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice . Science. 2006 Jul 28;313(5)


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