Seeking the Gears of Our Inner Clock.

Notes from Dr. Norman Blumenstock
Sleep and activity cycles are a very big part of psychiatric illnesses, reports the New York Times
Neuroscientists have struggled to understand exactly how the mind’s cycles affect us. Studies of donated brains provide some answers.

Carl Zimmer | DEC. 28, 2015

Throughout the day, a clock ticks inside our bodies. It rouses us in the morning and makes us sleepy at night. It raises and lowers our body temperature at the right times, and regulates the production of insulin and other hormones.

The body’s circadian clock even influences our thoughts and feelings. Psychologists have measured some of its effects on the brain by having people take cognitive tests at different times of day.

As it turns out, late morning turns out to be the best time to try doing tasks such as mental arithmetic that demand that we hold several pieces of information in mind at once. Later in the afternoon is the time to attempt simpler tasks, like searching for a particular letter in a page of gibberish.

“Sleep and activity cycles are a very big part of psychiatric illnesses,” said Huda Akil, a neuroscientist at the University of Michigan.

Yet neuroscientists have struggled to understand exactly how the circadian clock affects our minds. After all, researchers can’t simply pop open a subject’s skull and monitor his brain cells over the course of each day.

A few years ago, Dr. Akil and her colleagues came up with an idea for the next best thing.

The University of California, Irvine, stores brains donated to science. Some of their former owners died in the morning, some in the afternoon and others at night. Dr. Akil and her colleagues wondered if there were differences in the brains depending on the time of day the donors had died.

“Maybe it’s simple-minded, but nobody had thought of it,” Dr. Akil said.

She and her colleagues selected brains from 55 healthy people whose causes of death were sudden, such as in car crashes. From each brain, the researchers sliced tissue from regions important for learning, memory and emotions.

As each person died, his brain cells were in the midst of making proteins from certain genes. Because the brains had been quickly preserved, the scientists could still measure the activity of those genes at the time of death.

Most of the genes they examined didn’t show any regular pattern of activity over the course of the day. But they found that more than 1,000 genes followed a daily cycle. People who died at the same time of day were making those genes at the same levels.

The patterns were so consistent that the genes could act as a timestamp.

“We could ask, ‘What time did this person die?’” Dr. Akil said. “And we could pin it to within an hour of their actual recorded time of death.”

She and her colleagues then ran the same analysis on the brains of 34 people who had had major depression before dying. Now they found that the time stamp was wildly off the mark.

“It looked as if people were on Japan time or Germany time,” Dr. Akil said.

Dr. Akil and her colleagues published their results in 2013, inspiring researchers at the University of Pittsburgh School of Medicine to attempt to replicate them.

“It was something we didn’t think we could do before,” the neuroscientist Colleen A. McClung said.

Dr. McClung and her colleagues performed a bigger version of the study, examining 146 brains collected by the university’s donor program. The researchers published their results this week in The Proceedings of the National Academy of Sciences.

“Lo and behold, we got very nice rhythms,” Dr. McClung said. “It really seems like a snapshot of where the brain was at that moment of death.”

Dr. Akil is grateful that another team of researchers took the effort to back up her findings. “There is a lot of overlap, which makes you believe something is going on for real here,” she said.

But Dr. McClung and her colleagues also did something no one had. They compared the patterns of gene expression in the brains of young and old people and found intriguing differences.

The scientists hoped to find clues to why people’s circadian cycles change as they age. “As people get older, their rhythms tend to deteriorate and shift forward,” Dr. McClung said.

She found that some of the genes that were active in strong daily cycles in young people faded in people older than 60. It’s possible that some older adults stop producing proteins in their brains needed to maintain circadian rhythms.

To their surprise, however, the researchers also discovered some genes that became active in daily cycles only in old age. “It looks like the brain might be trying to compensate by turning on an additional clock,” Dr. McClung said.

Dr. Akil speculated that the brain’s ability to cobble together a backup clock might protect some older adults from neurodegenerative diseases. “It may spell the difference between deteriorating or not,” she said.

Eventually, it might even be possible to switch on our backup clocks as a way to treat a range of circadian-related disorders.

Dr. Akil said that finding clock-driven genes in human brains would help scientists running experiments on animals to figure out what those genes are doing.

“Instead of sitting in your lab imagining what genes might be important, here you’re taking your inspiration from the human brain and saying, ‘What is it trying to tell us?’” she said.