Brain’s Circadian Clock Disrupted in Depressed People
Major or clinical depression seems to alter the genes that regulate sleep and waking
Disrupted sleep is so commonly a symptom of depression that some of the first things doctors look for in diagnosing depression are insomnia and excessive sleeping. Now, however, scientists have observed for the first time a dysfunctional body clock in the brains of people with depression.
People with major depression, also known as clinical depression, show disrupted circadian rhythms across brain regions, according to a new study , researchers looked at post-mortem brain samples from mentally healthy donors and compared them with those of people who had major depression at the time of their death.
They found that gene activity in the brains of depressed people failed to follow healthy 24-hour cycles.
“They seem to have the sleep cycle both shifted and disrupted,” said study researcher Jun Li, a professor of human genetics at the University of Michigan.
The clockwork body
Everyone is born with a genome that acts as a blueprint for building the proteins that make up the body. But genes aren’t stable protein-building machines. Instead, they vary in their activity levels, expressing themselves more or less depending on the situation. One factor that influences gene expression is the daily light cycle.
In particular, cells in a region deep in the brain called the hypothalamus act as pacemakers, setting the body clock and keeping cells in the rest of the body on an approximately 24-hour cycle. The pacemaker cells explain why jet lag is such a pain: It takes time for this body clock to readjust in a new time zone.
To better understand how gene expression varies in depressed people, Li and his colleagues looked at the brains of 35 patients with major depression, and 55 mentally healthy people, all of whom had died at various points around the clock. The donated brains contained the fingerprint of gene expression at each time of death. Researchers examined this gene expression in six major brain regions: The dorsolateral prefrontal cortex, the amygdala, the cerebellum, the anterior cingulated cortex, the nucleus accumbens and the hippocampus.
In healthy people, a cycle clearly appeared. Those who had died around the same time of day showed similar patterns of gene expression across the brain.
“Some genes go high, low and high across the day” . “Others would be low, high and low.”
The patterns were so clear that the researchers could look at the gene expression in a brain and use the information to pinpoint time of death — but only in healthy brains. The depressed brains didn’t follow the healthy patterns.
For example, in healthy people, of the 16 genes that showed the clearest patterns of cycling, 11 genes cycled around the clock in four or more brain regions. By contrast, in people with major depression, only two of these genes showed clear cycling pattern in more than one region, and none cycled in more than three regions.
This lack of evidence of cellular cycling in depressed brains could have indicated that the depressed people’s circadian rhythms were simply flattened out, Li said. Or, the lack of pattern could reveal a shift in the daily cycle such that the patterns weren’t detectable in the depressed brains.
To test the idea, the researchers compared gene expression in depressed patients who died at different times, and found some similarities. That suggests that the depressed people’s body clocks may have been shifted by several hours, the researchers said.
Another analysis, however, found that genes that would be expected to shift together didn’t do so in depressed people. That finding suggested that the clocks were disrupted.
In other words, Li said, the problem in depressed brains appears to be both shifting and disruption.
“They seem to be sleeping at the wrong time of the day, and the quality of their sleep is also different from healthy sleep,” he said.
The sleep-cycle shift held in patients who had a diagnosis of major depression but who had not taken antidepressants before death, the researchers found, suggesting that it’s the disease itself and not the treatment that causes the circadian rhythm problems.
Already, symptoms of insomnia and excessive sleep in depressed people have inspired treatments such as light therapy to try to reset the body clock, Li said. The new research is confirmation that such approaches could work. Researchers might also be able to develop drug treatments to fix the body clock, he said.
“This reinforces the old idea that trying to address sleep cycle is a good practice in diagnosis and in treatment,” Li said.