Using mouse embryonic stem cells, Provencio, Kay and colleagues altered the gene to create a strain of mice that lacked a functioning gene for melanopsin. The mice appeared healthy and showed normal activity rhythms as they ran on wheels in constant darkness. This suggested that melanopsin is not involved in the normal functioning of the clock itself.

Then, the researchers exposed the melanopsin knockout mice to 15 minutes of blue light at a time in their cycle when normal mice show strong phase delays -- alterations in the time of onset of activity in response to light. The mice lacking melanopsin showed significantly less phase delay than normal control mice, likely because of reduced sensitivity in signals from the retina to the clock. To confirm this deficit in light input, the knockout mice were exposed to constant white light, which normally would trigger phase adjustments resulting in a longer internal clock day than in constant darkness. The melanopsin-deprived mice showed a shorter lengthening of their internal clock day than the control mice.

"Light input to the clock was significantly reduced in the melanopsin-deficient animals," said Provencio. "The sensitivity of their circadian system to light was reduced by 50 to 80 percent."

Although the study shows that melanopsin significantly influences the resetting of the clock at three different light intensities, exactly how this protein translates light into a neural signal isn't yet known.

The researchers propose that melanopsin is required for normal setting of the brain's clock by light, but that other mechanisms for light input also play a role, since the animals still show some phase shifting. As in plants and flies, "independent photoreceptors with overlap
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Contact: Jules Asher
NIMHpress@nih.gov
301-443-4536
NIH/National Institute of Mental Health
13-Dec-2002