Cellular-level connections provide potential targets for improved diagnosis and treatment

HUNTSVILLE, Ala. — Sleeping, eating, working; humans, as well as many other living organisms, have circadian patterns, regularly occurring, 24-hour rhythms, that are part of normal function.  Dysfunctions in regular patterns – such as insomnia and unexplained fluctuations in appetite, body temperature and/or hormones — are symptoms shared by many patients with depression.   Researchers at the HudsonAlpha Institute for Biotechnology, with scientists at the University of Michigan, the University of California at Irvine, Stanford University and Weill Cornell Medical College, collaborated in a study where they found the first direct evidence connecting cellular level activity in the brains of patients with depression to out-of-step circadian rhythms.  These groups have been part of the Pritzker Neuropsychiatric Disorders Research Consortium for the past decade.

“While these symptoms are easily discernable, the molecular basis of these symptoms in patients with major depressive disorder has been elusive,” said Rick Myers, Ph.D., president and director of HudsonAlpha and a leader of the Huntsville research group in this consortium.  “By examining postmortem brain samples of individuals who had not been diagnosed with depression, we found many genes showing a pattern of circadian rhythm.  We also found that genes involved in establishing and maintaining circadian rhythms are dysregulated in brains from people with major depressive disorder.”  By getting to the DNA-level activity inside brain cells, Myers added that researchers are providing new potential targets for diagnoses and treatments of MDD.

“There really was a moment of discovery,” says Jun Li, Ph.D., who is at the University of Michigan and led the analysis of the massive amount of data generated by the rest of the team.  “When we realized that many of the genes that we saw expressed in the healthy 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., co-director of the University of Michigan Molecular & Behavioral Neuroscience Institute and co-director of the University of Michigan site of the Pritzker Neuropsychiatric Disorders Research Consortium, said, “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.”

Why the circadian clock is altered in MDD remains elusive. “We can only glimpse the possibility that the disruption seen in depression may have more than one cause. 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,” added Akil.

Highly annotated samples were integral to the study and continue to be crucial in research going forward. The research team used material from the Pritzker Consortium Brain Bank led by William Bunney, M.D., at UC Irvine, a unique repository of donated brains obtained shortly after death.

The Pritzker Neuropsychiatric Disorders Research Fund was the major source of support for this research.  Additional funding was provided by the William Lion Penzner Foundation, the Della Martin Foundation, the Office of Naval Research, the National Alliance for Research on schizophrenia and Depression’s Abramson Family Foundation Investigator Award and an International Mental Health Research Organization—Johnson & Johnson Rising Star Translational Research Award.

The paper Circadian patterns of gene expression in the human brain and disruption in major depressive disorder, is published in the Proceedings of the National Academy of Sciences of the United States of America at http://www.pnas.org/content/early/2013/05/08/1305814110