Bmal1/Clock complex activates transcription of genes containing E-box sequences in their promoters. Among these are Per1/2 and Cry1/2, which following dimerization can inhibit the activity of the Bmal1/Clock complex. Rev-Erb and Ror provide an additional stabilizing loop to fine-tune the expression of Bmal1. In addition to E-boxes, other clock regulatory elements (such as ROREs and D-boxes) are commonly found in the promoters of CCGs.
Disruptions of daily rhythms of the body’s master internal clock 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 MDD, 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 Dr. Dominic Landgraf of UCSD
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.
They developed a new genetic mouse model by suppressing Bmal1, one of the master genes that drives circadian rhythms, in the suprachiasmatic nucleus (SCN), the brain’s central clock regulator. Lower Bmal1 expression reduced the strength of the clock signals produced by the SCN by ~80%. Targeting this particular brain region allowed them 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. http://www.alphagalileo.org/ViewItem.aspx?ItemId=170444&CultureCode=en
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