That syncing feeling

Seasonal rhythms affect gene expression in the brain; they also are linked with daily rhythms—and both are disrupted in Alzheimer's disease: study

Illustration: James Fryer

Above where the left and right optic nerves cross are two tiny structures that serve as command central for our brain’s internal “clock,” or circadian rhythm. The size of the head of a pin, these structures are called the suprachiasmatic [soo-pra-kī-az-ma-tik] nuclei. They contain thousands of neurons that receive information about light to help regulate sleep and wake patterns, body temperature and the release of hormones like melatonin and cortisol.

Circadian rhythms, which follow a 24-hour cycle, as well as seasonal rhythms, are found in all kinds of living things. “If you look across the animal kingdom, there are seasonal rhythms in animals that hibernate, and in plants with flowering and leaf growth. Similarly, there are circadian rhythms that permeate the natural world. Almost all animals have sleep and wake cycles,” says Dr. Andrew Lim, a neuroscientist at Sunnybrook Research Institute and neurologist at Sunnybrook.

An avid cyclist, Lim travels to work almost always on two wheels. (Only during snowstorms does he leave his bike at home.) Having just biked in, he is still in his cycling gear as we chat about his research. Lim notes that there are daily and seasonal rhythms in brain functions like mood and cognition; for instance, times of the day when people feel more alert. Another example of rhythmic brain function in action is seasonal affective disorder, a brain disease where people become profoundly depressed in the winter. Circadian and seasonal cycles are vital to our health, yet little is known about what drives them.

To shed light on the biology behind these rhythms, Lim and his colleagues in the U.S. analyzed the brains of 757 deceased people who volunteered for long-term studies on aging and memory. In particular, the team examined patterns of gene expression in a brain region that’s important for thinking and mood. They used a technique called RNA sequencing, which is a read-out of all the RNA in a cell. Since RNA mirrors the DNA from which it was copied, RNA sequencing can tell researchers where a gene is turned on or off, and the amount of gene activity, or expression. With this technology he and his colleagues were able to assess the levels of expression for every single gene in the genome in each brain. “We were able to construct a chart for each one of the 20-something-thousand genes, showing what the pattern of expression of that gene is across the day. Is it higher at night, in the morning, or in the afternoon?” says Lim, who is also an assistant professor of medicine at the University of Toronto.

The first thing they found is that there are indeed seasonal rhythms of gene expression. This discovery had never before been made in any human organ, and suggests there is a biological basis for brain disorders that are influenced by the seasons. “Nobody had ever asked the question whether our brains, at a deep molecular level, are different in the winter than in the summer. It isn’t that we merely feel different; our brains are fundamentally different at different times of the year, and at different times of the day,” says Lim. Next, they discovered that daily and seasonal regulation of genes were tightly linked, so much so that “you could, to some degree, predict how a gene would behave across seasons if you knew how that gene behaved across the day and night cycle,” he says.

The team also found there were differences in the timing of gene expression in the brains of people who had Alzheimer’s disease (AD) compared to those that didn’t have the disease. Daily rhythms of gene expression in people with AD were advanced by one-and-a-half hours, while seasonal rhythms were delayed by two weeks. Abnormal rhythms of gene expression in AD may account for difficulties with sleep and increased behavioural problems that begin late in the day, says Lim.

Our brains are fundamentally different at different times of the year, and at different times of the day.

The groundbreaking study opens up different avenues of research into the biology of daily and seasonal rhythms. Basic scientists can look at gene expression patterns across days and seasons in preclinical models to uncover the specific mechanisms regulating those patterns. Meanwhile, translational researchers, who have clinical impact in mind, can look for changes in gene expression in conditions like seasonal affective disorder to identify genes linked to the disease that could serve as drug targets.

The capacity to examine gene expression in the human brain was a confluence of favourable circumstances, Lim notes. The study hinged on access to a large sample of postmortem brain tissue. Moreover, only in the last few years has the technology to do RNA sequencing at a global level become available. Finally, he and his lab were able to engineer tools to process staggering amounts of data. “Each analytic run could take many days to a week at a dedicated super-computing facility. A lot of the work we did was to develop the algorithms to make it possible to do this large-scale data analysis even with the latest in computing tools,” says Lim.

Computer programming and data analysis are major aspects of his group’s research. He is leading the Ontario Sleep and Brain Health Study, which looks at the impact of sleep on cognition. His team is examining sleep patterns of people in their thirties and forties to determine whether insufficient shuteye is linked to changes like damage to blood vessels in the brain and brain shrinkage. He is also studying whether poor sleep has an immediate effect on mental performance and if it increases the risk of dementia long-term. “The big issue is that nobody sleeps enough,” says Lim. He acknowledges that his own sleep is erratic because he works on call overnight every week. He is not alone. Parents of young children and people who do shift work also tend to have irregular sleep patterns.

Research Lim published in 2013 has already established a link between sleep disruption in older adults and increased risk of AD. Thanks to studies like this, more people are appreciating the importance of a good night’s slumber.

It’s about time.

— Alisa Kim

Lim’s research is supported by the Canadian Institutes of Health Research, National Institutes of Health, and Ontario Ministry of Research, Innovation and Science.