Bad timing is depressing: Disrupting the brain’s internal clock causes depressive-like behavior in mice
Philadelphia, PA, November 29, 2016 – Disruptions of daily rhythms of the body's master internal clock cause depression- and anxiety-like behaviors in mice, reports a new study in Biological Psychiatry. The findings provide insight into the role of the brain's internal time keeping system in the development of mood disorders, such as bipolar disorder and major depressive disorder, which have been associated with disturbed daily (circadian) rhythms.
"Our data show that perturbing circadian rhythms in otherwise totally undisturbed animals is enough to cause behaviors similar to human depression," commented first author Dr. Dominic Landgraf of the University of California, San Diego.
Inherent circadian clocks help us function throughout the day, by telling us when to sleep, wake and eat, as well as by synchronizing our bodily processes. "It is perhaps not surprising that disruptions of our natural synchronization can have heavy impacts on our physical and mental health," Dr. Landgraf added.
However, until now researchers did not know if disturbed circadian rhythms were a cause or consequence of mood disorders. In the new study, a team led by David K. Welsh has shown for the first time a causal relationship between functioning circadian clocks and mood regulation.
The researchers developed a new genetic mouse model by suppressing Bmal1, one of the master genes that drives circadian rhythms, in the suprachiasmatic nucleus (SCN), which serves as the brain's central clock regulator. Diminished Bmal1 expression reduced the strength of the clock signals produced by the SCN by about 80%. Targeting this particular brain region allowed the researchers to focus on the specific effects of the SCN circadian rhythms, and to avoid alterations in other brain regions that have confounded previous studies.
In behavioral tests, mice with reduced circadian rhythms, relative to control mice, were less motivated to escape an uncomfortable situation, which is commonly interpreted as despair or hopelessness in the animal. The mice also showed increased aversion to brightly lit areas, considered to be an indicator of anxiety-like behavior.
In addition to the altered behavior, mice with reduced circadian rhythms gained more weight than normal mice, even though they consumed the same amount of food. This finding suggests that disrupted SCN circadian rhythms could lead to metabolic abnormalities observed in many depressed patients.
Importantly, the findings show that even though the SCN does not directly regulate mood, alterations to circadian rhythms in the SCN are sufficient to cause depression- and anxiety-like behaviors in mice.
"We have long known that disruptions in circadian rhythms may contribute to depression, particularly in people at risk for major depression or bipolar disorder," said Dr. John Krystal, Editor of Biological Psychiatry. "This new study provides additional evidence implicating the Bmal1 gene in the relationship between these circadian rhythms and mood."
According to Dr. Landgraf, the results are an important step toward developing new depression treatments that directly target the circadian clock in humans.
Notes for editors
The article is "Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice," by Dominic Landgraf, Jaimie E. Long, Christophe D. Proulx, Rita Barandas, Roberto Malinow, and David K. Welsh (doi: 10.1016/j.biopsych.2016.03.1050). It appears in Biological Psychiatry, volume 80, issue 11 (2016), published by Elsevier.
Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at +1 214 648 0880 or [email protected] Journalists wishing to interview the authors may contact Dominic Landgraf, Ph.D. at [email protected]
The authors' affiliations, and disclosures of financial and conflicts of interests are available in the article.
John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.
About Biological Psychiatry
Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.
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