In the first in vivo study of its kind, researchers show that the pattern of neural activity in the brain's circadian hub—the suprachiasmatic nucleus (SCN)—begins to decay as mice hit middle age, though the expression of a clockwork gene in the SCN remains unaffected. The findings, published today (July 12) in The Journal of Neuroscience, provide a sketch of the possible sequence of events that contribute to sleep troubles of the elderly.

“Surprisingly to us, at least to the point that we looked, we did not see any major deficits in gene expression. So the molecular clockwork is working fine, but the neural activity is running down,” said Christopher Colwell, a professor in UCLA's School of Medicine and one of the authors of the study.

“Even though the gene expression is normal, that doesn't mean the clock isn't aging,” added Fred Turek, the director of...

The aging of the circadian clock is thought to underlie the common sleep maladies older people experience, Colwell said. “More or less, one of the things we can count on [as we age] is going to bed earlier, waking up earlier, waking up during the night, and having difficulty staying awake during the day.”

Mice too experience circadian disturbances as they age. Colwell's group observed that young mice (aged 2-4 months) consistently ran on the wheel during dark periods, while middle-aged mice (12 months old) had more fragmented spurts of running, and they ran less vigorously.

Those activity patterns, the researchers learned, reflect changes in the neural firing patterns of the SCN, a brain region long touted as the master regulator of circadian rhythms. For more than a month, Colwell and his colleagues recorded activity from neurons in the SCN while the mice behaved normally. In young mice, the neural firing followed a clear pattern of high during light periods and low during dark periods, when the mice are most active. In middle-aged mice, the circadian pattern was a lot less consistent, with the SCN showing a broader range of activity levels during dark and light cycles. On average, the ratio of neural activity between light and dark cycles in young mice was double that of middle-aged mice, confirming in vivo what others have found in a dish.

“I think that's the most important part of the paper, showing that the amplitude of the clock itself is reduced,” said Turek. “This could be an underlying cause in a number of age-related changes in [circadian] rhythm.”

In contrast to previous studies, however, which reported age-related disruptions in the rhythmic expression of the clockwork protein PER2, the researchers found no differences in PER2 expression in the SCN between young and middle-aged mice. Consistent PER2 expression in the face of changing SCN  activity illustrates that “we don't know the full relationship between the firing activity and the molecular clockwork,” Stephany Biello, a University of Glasgow professor who did not participate in the research, told The Scientist.

With gene expression ruled out, it remains unclear what molecular mechanisms contribute to the changes in the SCN in older mice—a question Colwell and his colleagues plan to investigate. “We don't know the answer, but we're very interested in following up [on] that,” Colwell said.

T.J. Nakamura, et al., “Age-related decline in circadian output,” The Journal of Neuroscience, 31(28):10201–5, 2011.

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