Depression: Patients Body Clocks are Altered at Cell Level

The researchers used gene expression patterns to try to predict the time of death for each person in the study (inner circles), and then compared it with the actual time of death (outer circles). 

The two matched closely in healthy people, as shown by the short lines between the two points in the left diagram. 

But in depressed people, the two were out of sync, as seen with the longer lines at right. 

Credit: Image courtesy of University of Michigan Health System

Every cell in our bodies runs on a 24-hour clock, tuned to the night-day, light-dark cycles that have ruled us since the dawn of humanity.

The brain acts as timekeeper, keeping the cellular clock in sync with the outside world so that it can govern our appetites, sleep, moods and much more.

But new research shows that the clock may be broken in the brains of people with depression -- even at the level of the gene activity inside their brain cells.

It's the first direct evidence of altered circadian rhythms in the brain of people with depression, and shows that they operate out of sync with the usual ingrained daily cycle.

The findings, in the Proceedings of the National Academy of Sciences, come from scientists from the University of Michigan Medical School and other institutions.

The discovery was made by sifting through massive amounts of data gleaned from donated brains of depressed and non-depressed people.

With further research, the findings could lead to more precise diagnosis and treatment for a condition that affects more than 350 million people worldwide.

What's more, the research also reveals a previously unknown daily rhythm to the activity of many genes across many areas of the brain -- expanding the sense of how crucial our master clock is.

In a normal brain, the pattern of gene activity at a given time of the day is so distinctive that the authors could use it to accurately estimate the hour of death of the brain donor, suggesting that studying this "stopped clock" could conceivably be useful in forensics.

By contrast, 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.

Read more of this article here

Journal Reference:

1. Jun Z. Li, Blynn G. Bunney, Fan Meng, Megan H. Hagenauer, David M. Walsh, Marquis P. Vawter, Simon J. Evans, Prabhakara V. Choudary, Preston Cartagena, Jack D. Barchas, Alan F. Schatzberg, Edward G. Jones, Richard M. Myers, Stanley J. Watson, Jr., Huda Akil, and William E. Bunney. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. PNAS, 2013 DOI: 10.1073/pnas.1305814110

Sleep: Biologists uncover the dynamic between biological clock and neuronal activity

Biologists at New York University have uncovered one way that biological clocks control neuronal activity -- a discovery that sheds new light on sleep-wake cycles and offers potential new directions for research into therapies to address sleep disorders and jetlag.

"The findings answer a significant question -- how biological clocks drive the activity of clock neurons, which, in turn, regulate behavioural rhythms," explained Justin Blau, an associate professor in NYU's Department of Biology and the study's senior author.

Their findings appear in the Journal of Biological Rhythms.

Scientists have known that our biological clocks control neuronal activity but not previously understood is how this process occurs -- that is, how does information from biological clocks drive rhythms in the electrical activity of pacemaker neurons that, in turn, drives daily rhythms?

To understand this mechanism, the researchers examined the biological, or circadian, clocks of Drosophila fruit flies, which are commonly used for research in this area.

Earlier studies of "clock genes" in fruit flies allowed the identification of similarly functioning genes in humans.

In their study, the researchers focused on eight master pacemaker neurons located in the central brain -- these neurons set the timing of the daily transitions between sleep and wake in the fly.

Specifically, they were able to isolate these neurons from animals and identify sets of genes differentially expressed between dawn and dusk.

In a series of follow-up experiments, they concentrated on one gene, Ir, whose expression was found to be much higher at dusk than at dawn and much more highly expressed in pacemaker neurons than in the rest of the brain.

Ir encodes a potassium channel that helps set the resting state of neurons -- and so its rhythmic expression makes it an excellent candidate to help link the biological clock to pacemaker neuron activity.

High levels of Ir expression at dusk should make it much harder for pacemaker neurons to signal than the low levels seen at dawn, a finding that fits with earlier studies showing that pacemaker neurons fire more at dawn than at dusk.

The authors also found that genetic manipulations that either increase or decrease Ir levels affect behavioral rhythms. Perhaps more interestingly, these were also associated with changes in the timing and strength of oscillations in the core clock.

"Biology is never as simple as we imagine it will be," explained Blau. "We were looking for an output of the biological clock that would link the core clock to neuronal activity. Ir seems to do this, but it also, remarkably, feeds back to regulate the core clock itself. Feedback loops seem to be deeply engrained into the biological clock and presumably help these clocks work so well."