Retinal clock regulates vision

The mammalian retina contains its own circadian clock that processes visual information without input from the master circadian clock in the brain, according to a report in this week's Cell. This clock may allow the retina to adjust its sensitivity to light by anticipating daily cycles of light and darkness. The mammalian master circadian clock lies in the suprachiasmatic nucleus (SCN) of the brain, but other tissues also show circadian oscillations in gene expression. "This is really important, because this is one of the few papers that actually shows a physiological role for the circadian clock outside of the suprachiasmatic nucleus," said Gianluca Tosini of Morehouse School of Medicine in Atlanta, Ga., who was not involved in the work. Previous work has shown that there are circadian rhythms in visual sensitivity and retinal electrical responses, said Michael Iuvone of Emory University in Atlanta, Ga., who was not involved in the study. These rhythms are thought to allow the retina to anticipate illumination changes between night and day and to adapt to them before they occur. But "it was never really known if it was a retinal clock that was generating that or if it's the clock in the suprachiasmatic nucleus feeding back onto the retina," Iuvone told The Scientist.Researchers led by Kai-Florian Storch and Carlos Paz of Harvard Medical School in Boston, Mass., first conducted a whole-genome microarray in mice to find retinal genes whose expression levels cycle approximately every 24 hours. They discovered nearly 300 genes with circadian expression patterns when the mice were kept in darkness. When the animals were exposed to normal daily cycles of light and darkness, more than 2,500 genes revealed circadian expression patterns. The researchers next examined mice missing a key circadian gene called Bmal1. These mice showed abnormal expression of 90% of the genes with circadian expression patterns during light-dark cycles. They also found that retinal physiology was abnormal in these mice. While photoreceptor responses were normal, the electrical impulses that transmit photoreceptor information to the inner retina were significantly reduced in Bmal1 knockouts. This reduction in electrical activity was more pronounced in animals adapted to the light, compared with those adapted to the dark. The researchers also found that the SCN was not necessary for any of these effects. When they lesioned the SCN, the mice displayed the same dampening of retinal electrical signals.The researchers next created a mouse with Bmal1 knocked out exclusively in the retina. These animals showed normal circadian gene expression everywhere except in the retina. Just as in mice missing Bmal1 everywhere, retina-specific knockouts showed abnormally low electrical activity in the inner retina, especially when they were exposed to light. Knocking out Bmal1 specifically in the retina "pretty much nails it that it's the retinal clock that's regulating the daily rhythms in visual processing," and not the SCN, said Iuvone. The SCN lesion experiments also confirm this conclusion, said Joseph Besharse of the Medical College of Wisconsin in Milwaukee, who was not involved in the work. It's possible that disrupting retinal circadian rhythms could actually affect the SCN clock, he added. "It will be interesting to see."Peripheral oscillators in other tissues may not show the same independence as that in the retina, Iuvone said. "Most circadian rhythms in peripheral tissues disappear when you lesion the suprachiasmatic nucleus," he said. "The retinal clock may be a little bit unique."Melissa Lee Phillips mail@the-scientist.comLinks within this articleL. Hrastar, "Opsin mediates circadian clock," The Scientist, January 28, 2005. http://www.the-scientist.com/news/20050128/02/E. Russo, "Circadian rhythm homology and divergence," The Scientist, July 10, 2000. http://www.the-scientist.com/article/display/11941/K-F Storch et al., "Intrinsic circadian clock of the mammalian retina: importance for retinal processing of visual information," Cell, August 24, 2007. http://www.cell.comR. Barlow, "Circadian and efferent modulation of visual sensitivity," Progress in Brain Research, 2001. http://www.the-scientist.com/pubmed/11420965K.Y. Kreeger, "Collecting clues to the mammalian clock," The Scientist, April 15, 2002. http://www.the-scientist.com/article/display/12992/C.H. Ko and J.S. Takahashi, "Molecular components of the mammalian circadian clock." Human Molecular Genetics, October 15, 2006. http://www.the-scientist.com/pubmed/16987893S. Yamazaki et al., "Resetting central and peripheral circadian oscillators in transgenic rats." Science, April 28, 2000. http://www.the-scientist.com/pubmed/10784453Gianluca Tosini http://web.msm.edu/nasa/tosini.htmMichael Iuvone http://www.biomed.emory.edu/FacSearch/fac_profile.cfm?CFID=5337609&CFTOKEN=68142760&faculty_id=1103 G. Tosini and C. Fukuhara, "The mammalian retina as a clock," Cell and Tissue Research, July 2002. http://www.the-scientist.com/pubmed/12111542Kai-Florian Storch http://www.researchmatters.harvard.edu/people.php?people_id=546N. Gekakis et al., "Role of the CLOCK protein in the mammalian circadian mechanism," Science, June 5, 1998. http://www.the-scientist.com/pubmed/ 9616112Joseph Besharse http://www.mcw.edu/display/router.asp?docid=16420

Retinal clock regulates vision

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