Study finds circadian clock rhythms altered in depression
UC Irvine Health researchers have helped discover that genes controlling circadian clock rhythms are profoundly altered in the brains of people with severe depression. These clock genes regulate 24-hour circadian rhythms affecting hormonal, body temperature, sleep and behavioral patterns.
Depression is a serious disorder with a high risk for suicide affecting approximately one in 10 Americans, according to the Centers for Disease Control, and is ranked as fourth of all diseases by the World Health Organization in terms of lifetime disability. Study findings provide the first evidence of altered circadian gene rhythms in brain tissue of people with depression and suggest a physical basis for many of the symptoms that depressed patients report.
The study – which appears online this week in the Proceedings of the National Academy of Sciences – involved researchers from UC Irvine Health, University of Michigan, UC Davis, Cornell University, the Hudson Alpha Institute for Biotechnology and Stanford University.
“Our findings involved the analysis of a large amount of data involving 12,000 gene transcripts obtained from donated brain tissue from depressed and normal people. We were amazed that our data revealed that clock gene rhythms varied in synchrony across six regions of normal human brain and that these rhythms were significantly disrupted in depressed patients. The findings provide clues for potential new classes of compounds to rapidly treat depression that may reset abnormal clock genes and normalize circadian rhythms,” said Dr. William Bunney, the study’s senior author, and Distinguished Professor of Psychiatry & Human Behavior at UC Irvine.
Circadian clock genes play an important role in regulating many body rhythms over a 24-hour cycle. Although animal data provide evidence for the circadian expression of genes in brain, little has been known as to whether there is a similar rhythmicity in the human brain.
In the study, the researchers analyzed genome-wide gene expression patterns in brain samples from 55 individuals with no history of psychiatric or neurological illness and compared them to the expression patterns in samples from 34 severely depressed patients.
Lead author Jun Li, Ph.D., an assistant professor in the U-M Department of Human Genetics, describes how this approach allowed the team to accurately back-predict the hour of the day when each non-depressed individual died - literally plotting them out on a 24-hour clock by noting which genes were active at the time they died. They looked at 12,000 gene transcripts isolated from six regions of 55 brains from people who did not have depression.
This provided a detailed understanding of how gene activity varied throughout the day in the brain regions studied. 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.
“There really was a moment of discovery,” says Li, who led the analysis of the massive amount of data generated by the rest of the team and is a research assistant professor in U-M’s Department of Computational Medicine at Bioinformatics. “It was when we realized that many of the genes that show 24-hour cycles in the normal individuals were well-known circadian rhythm genes - and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity. It’s as if they were living in a different time zone than the one they died in.”
Huda Akil, Ph.D., the co-director of the U-M Molecular & Behavioral Neuroscience Institute and co-director of the U-M site of the Pritzker Neuropsychiatric Disorders Research Consortium, notes that the findings go beyond previous research on circadian rhythms, using animals or human skin cells, which were more easily accessible than human brain tissues.
“Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research - not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day,” she says. “We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted.”
The investigators isolated multiple RNA samples from six regions of each brain and arranged the gene expression data around a 24-hour cycle based on time of death. Several hundred genes in each of six brain regions displayed rhythmic patterns of expression over the 24-hour cycle, including many genes essential to the body’s circadian machinery.
Some of the clues that circadian rhythms are disrupted in people with mood disorders are:
- Lack of sleep can trigger mania or hypomania in people with bipolar disorder. Interestingly, intentional sleep deprivation can also lead to short term mood improvement in people with depression.
- A common symptom of depression is “early morning awakening” i.e. waking up several hours earlier than usual and not being able to get back to sleep. A person who has early morning awakening when they are depressed often also has less appetite than usual when they are depressed.
- A smaller group of people with depression have the opposite pattern of wanting to sleep a lot and feeling more hungry than usual.
- People who have mood disorders tend to have more sleep difficulties outside of their mood disorder episodes compared to people who have never been depressed.
- Sleep symptoms are often one of the last symptoms to “come right” when someone is recovering from depression.
- One type of depression is Seasonal Affective Disorder (SAD), in which people have difficulty adjusting to the onset of winter. (There is also a spring/summer version of SAD but its far less common than the winter version).
- Lots more.
In the end, they had a near-complete understanding of how gene activity varied throughout the day in the cells of the six brain regions they studied.
“There really was a moment of discovery when we realized that many of the genes that we saw expressed in the normal individuals were well-known circadian rhythm genes – and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity,” said Jun Li, an assistant professor in the Department of Human Genetics at the University of Michigan who led the analysis of the massive amount of data generated by the rest of the team.