Foundation Grantees Identify Brain Genes Linked to Body Clock Disruption in Depression

Jun Z. Li, Ph.D., University of Michigan, depression expert
Jun Z. Li, Ph.D.
New Brain & Behavior Research Foundation-supported research finds evidence of altered “circadian rhythms” (the biological 24-hour clock that governs the function of every cell in our body) in the brain of people with depression. Foundation Grantees Jun Z. Li, Ph.D., Simon J. Evans, Ph.D. and Stanley J. Watson, M.D., Ph.D. and Foundation Scientific Council Members Huda Akil, Ph.D., Jack D. Barchas, M.D., Alan F. Schatzberg, M.D., and William E. Bunney, Jr., M.D. went beyond previous research that used animal or human skin cells to analyze post-mortem brain tissue. The results of their work were published April 3, 2013 in the Proceedings of the National Academy of Sciences.
The researchers compared data derived from samples taken from post-mortem brains of 34 people with a history of Major Depressive Disorder to that of 55 subjects who did not have a history of mental or neurological illness. They sought to pinpoint differences in gene expression to find evidence of normal and “off sync” patterns of rhythm and synchronization in six brain regions. Using lasers to capture specialized cell types and advanced data-mining tools to sift through massive amounts of data, they found that 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. 
"There really was a moment of discovery," according to lead author and 2009 NARSAD Young Investigator Grantee Jun Li, Ph.D., Assistant Professor, Department of Human Genetics and Department of Computational Medicine at Bioinformatics, University of Michigan (U-M). "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."
Foundation Scientific Council Member 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, says of the team’s findings:"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."
Now, she adds, scientists can use this information to potentially identify biomarkers―or biological predictors―for depression that can be found in blood, skin or hair samples. It can also help fine-tune treatments for individual patients and develop newly targeted treatments.