Gene activity in the brain suggests off-kilter circadian rhythms
The disruption of sleep and other bodily rhythms that often accompanies clinical depression may leave a mark on the brain. A study of gene activity in the brains of people who suffered from depression reveals that their daily clocks were probably out of whack. The results appear May 13 in the Proceedings of the National Academy of Sciences.
“This is really important work, amazing work,” says Noga Kronfeld-Schor, a physiologist who specializes in circadian rhythms at Tel Aviv University. “There’s been indirect evidence, but this clearly shows a connection between disrupted circadian cycles and depression.”
In mammals, daily rhythms such as sleep, hormone cycles and eating patterns are guided by a master clock in the brain whose rhythms are maintained in part by genes and patterns of light and darkness. The master clock can get out of sync with clocks elsewhere in the brain and body. This discord, for example, produces the out-of-sorts feeling of jet lag, says Jun Li, a statistical geneticist at the University of Michigan in Ann Arbor.
People with depression also often have off-kilter body rhythms. But the molecular and cellular mechanisms behind these disrupted cycles have been hard to pin down. Li and his colleagues took an ambitious approach with an unusual set of samples: the brains, removed just after death, of 34 people with depression and 55 people who didn’t suffer from depression. All of the people had died suddenly, from heart attacks or suicide, for example, and each brain was immediately put on ice, Li says.
After determining how long after sunrise each person’s death was, the team looked at what genes were turned on in six brain regions, gathering a total of 12,000 records of gene activity. Among nondepressed people, patterns were pretty predictable. One gene’s activity, for example, consistently peaked at sunrise, another's at midday, Li says. But in the depressed brains, gene activity seemed uncoupled from time of day. Their patterns of activity also weren’t as predictable.
The research doesn’t demonstrate whether depression causes the circadian disruption or vice versa, but it confirms a link and might lead to investigations of the physiological processes that are affected, says Ying-Hui Fu a molecular biologist and geneticist at the University of California, San Francisco.
Each brain analyzed in the study shows gene activity at only one point, the time of death. Circadian rhythm researchers typically take measurements from a person over the course of 24 hours. That strategy works for sampling blood cells, for example, but not brains. The brain data, which were collected with the help of collaborators at several universities including the brain bank at the University of California, Irvine, isn’t perfect but is impressive, Fu says.
“The data set is very solid,” Fu says. “And to collect 30 to 50 brains? Just getting blood or cheek cells is hard enough.”
Jun Z. Li et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proceedings of the National Academy of Sciences. Published May 13, 2013. doi:10.1073/pnas.1305814110.