Doesn’t quite run like clockwork when we are depressed (Image: Clay Patrick McBride/Photonica/Getty)

Genes in cells throughout the body switch on and off throughout the day in a coordinated way. Or at least they should. In people with clinical depression, genes in their brain tissues appear to be significantly out of sync – a finding that could lead to new treatments for the condition.

We know from previous studies that genes in cells elsewhere, such as the skin, follow a 24-hour cycle of activity. But identifying patterns of genetic activity in a living brain isn’t easy to do.

“We always assumed we would have a clock [in our brain],” says Huda Akil at the University of Michigan in Ann Arbor. “But it had never been shown before.”


Akil and her colleagues examined the brains of 55 people with a known time of death, looking at around 12,000 genes in tissues from six brain regions. By matching the time of death with molecular signs of genetic activity – whether each gene was actively expressing itself or not – the team identified hundreds of genes that follow a daily cycle.

Sudden death

Akil says it was important to look at the brains of individuals who had died suddenly – through a heart attack or car accident, for example. Slower deaths can cause dramatic changes in the brain that would have obscured what they were looking for, but sudden death freezes the genetic activity. “We can capture an instant,” she says.

Once the team had a record of how these genes work together like an intricate set of gears, with different but coordinated timings, they found they could read a given snapshot of genetic activity like a clock. This meant that by examining the genetic state of the brain in someone who had recently died, the team could correctly determine the time of death – unless that person had depression.

When the team looked at the brains of 34 people who had been diagnosed with major depressive disorder before they died, they found that far fewer genes followed a regular cycle, and many of those that did were out of phase. “It was as if they were in a different time zone,” says Akil.

Akil hopes that the findings could lead to the development of new drugs that might help doctors reset this out-of-sync biological clock in people with depression.

Disrupted sleep patterns are a common symptom of clinical depression, says Derk-Jan Dijk, director of the Sleep Research Centre at the University of Surrey in Guildford, UK, who was not involved in the work. “But it may not be the clock genes driving behaviour,” he says. “It may be the other way around.” He hopes more studies of this kind will make the activity cycles of individual genes clearer.

Master clock not included

Dijk also notes that the study does not have data from the suprachiasmatic nucleus (SCN) – the part of the brain thought to be the body’s master clock. Akil says she wishes that the team had been able to study this region. “It’s a heartbreaker it’s not in there,” she says. But the SCN sits deep in the brain and proved too hard to reach. “It gets torn as the brain is lifted from the skull,” says Akil.

Akil and colleagues are now working on a way to monitor clock genes in the brain without having to dissect it. They have taken samples of blood and skin cells from the people whose brains they studied, and hope to generate stem cells from these samples to grow specific types of brain cell in the lab. By comparing their record of the timing of gene activity in someone’s brain with that of genes in lab-grown brain tissue derived from the same person, the researchers may be able to learn to identify the signs of a disrupted clock in living patients. As Akil puts it, the idea is to look at a living person and ask: “Is their clock broken?”

Journal reference: PNAS, DOI: 10.1073/pnas.1305814110