Out of sync with the world: Brain study shows body clock is “broken” in depression

The internal circadian rhythm "clock", based in the brain, rules many body functions

The internal circadian rhythm “clock”, based in the brain, rules many body functions

Every cell in our bodies runs on a 24-hour clock, tuned to the night-day, light-dark cycles that have ruled us since the dawn of humanity.

Our brain acts as timekeeper, keeping that clock in sync with the outside world. It rules our appetites, our sleep, our moods and much more.

But new research led by U-M Medical School scientists shows that the clock may be broken in the brains of people with depression — even at the level of the gene activity inside their brain cells.

It’s the first time this has ever been seen directly.

Circadian rhythms out of whack

The team published its findings in a major scientific journal on Monday. To get there, they had to sift through massive amounts of data from donated brains of depressed and non-depressed people.

Now, they hope their findings could lead to more precise diagnosis and treatment for depression, which affects more than 350 million people worldwide.

What’s more, the research also reveals a previously unknown daily rhythm to the activity of many genes across many areas of the brain – expanding the sense of how crucial our master clock is.

In a normal brain, the pattern of gene activity at a given time of the day is so distinctive that the authors could use it to accurately estimate the hour of death of the brain donor, suggesting that studying this “stopped clock” could conceivably be useful in forensics.

But in severely depressed patients, the circadian clock was so disrupted that a patient’s “day” pattern of gene activity could look like a “night” pattern — and vice versa.

circadian depression diagram no sun

The researchers used gene expression patterns to try to predict the time of death for each person in the study (inner circles), and then compared it with the actual time of death (outer circles). The two matched closely in healthy people, as shown by the short lines between the two points in the left diagram. But in depressed people, the two were out of sync, as seen with the longer lines at right.

Science that may help depression patients

The discovery wouldn’t have been possible without donated brains, sophisticated DNA equipment, powerful computers, and funding from the federal government and the private Pritzker Neuropsychiatric Disorders Research Fund.

Scientist Jun Li, Ph.D., says this combination of scientific tools and expertise allowed the team to figure out the hour of the day when the 55 non-depressed people in the study died, based on which genes were active at the time they died. These predicted times matched well with the actual times of death.

But when the team tried to do the same in the brains of 34 depressed individuals, the gene activity was off by hours. The cells looked as if it were an entirely different time of day from when the person actually died.

“The people with depression were not synchronized to the usual solar day in terms of their gene activity. It’s as if they were living in a different time zone than the one they died in,” says Li.

Huda Akil, Ph.D., who co-directs U-M’s neuroscience institute, says the discovery opens up all kinds of questions about why these circadian rhythm changes happen – and what might be done about it.

“We need to learn more about whether something in the nature of the clock itself is affected, because if you could fix the clock you might be able to help people get better,” she notes.

Read more about this discovery


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