A Circadian Conundrum: Sleep and the Suprachiasmatic Nucleus

Insomniacs have it rough: imagine a long day of tedious work and activities after which you come home to even more chores.  Exhaustion finally sets in, and you are ready to collapse into bed, eagerly looking forward to those precious hours of sleep when you can finally rest your mind and body.  Yet, as the hours tick by on your bedside clock, you find yourself still awake. Drifting in and out of sleep, not only are you not energized the next day, but also even more exhausted.  The worst thing about this scenario?  It happens every night.

According to a recent National Sleep Foundation survey, approximately one-third of the American population today does not receive a sufficient amount of sleep (1). Even more problematic are the consequences of inadequate sleep: poor health, inefficiency and low productivity, to name a few. Treatment for sleep disorders is often limited to medication since the biology of sleep is a relatively new area of research. However, mathematician Daniel Forger and graduate student Casey Diekman at the University of Michigan just might have changed that. In October 2009, they, along with Dr. Mino Belle and Hugh Piggins from the University of Manchester, overturned a long-held theory about the human body’s internal timekeeping system, which controls sleep patterns. While their challenge provokes even more questions about this system, it could also lead to an ultimate answer for the treatment of sleep disorders.

The suprachiasmatic nucleus, or SCN, is located in the hypothalamus and controls the body’s metabolic rate. Regarding circadian patterns, thoughts have centered on the idea that circadian changes result from differences in SCN neural firing rates, which increase and decrease during the day and at night, respectively. These thoughts have recently come to focus on the synthesis of proteins like PER by the per gene, short for “period,” which are considered essential to the proper function of SCN cells. PER, along with complementary TIM (timeless) proteins, which are produced by the tim gene, participate in a feedback loop that detects changes in the time of day (2, 3). PER and TIM proteins attach to form a PER-TIM complex. Though both PER and TIM proteins are made during the day, at night, when a certain concentration of PER protein is reached, TIM protein binds to PER protein to form the PER-TIM complex, inhibiting further synthesis of PER protein.  At this time, per and tim genes become more active. This inhibition and consequent activation signifies a time change.  The biological clock is “set,” therefore, by this inhibition-based change in PER protein concentration, which generally occurs at semi-regular intervals each day. A decrease in PER and TIM production leads to an increase in protein complexes as well as SCN neural firing, which in turn results in amplified physiological awareness.

Historically, attempts have been made to create models to study these types of signals. Experiments have typically been based on  examining electrical impulses from both “clock” cells, those which contain the Per1 gene, and “non-clock” cells, those which do not contain Per1 (4). Now, researchers like Belle and Piggins have managed to separate these two types and study just the clock cells, but in mice, whose biological mechanisms are similar to those of humans. Clock cells were found to endure electrical levels that most neurons, like non-clock cells, cannot (5). Electrophysiology revealed that the SCN clock cells “expressing Per1 sustain an electrically excited state” without firing until first, dusk, and then once again at dawn (4). Consequently, this experiment, published in the October 9, 2009 issue of Science, reveals that circadian rhythms are not based on changing amounts of firing, but on the specific firing times of the Per1 containing clock cells.

No matter how exciting the news, however, there is a downside: new breakthroughs often lead to even more questions about the subject. Scientists at Washington University in St. Louis recently published a study in Proceedings of the National Academy of Sciences in which they describe the unreliability of SCN cells. According to this study, conducted by neuroscience graduate student Alexis Webb, professors Erik Herzog and James Huettner and biology undergraduate Nikhil Angelo,  SCN cells are unstable in their synchronization and easily become disrupted  in their oscillations (6).  This same disruption and ease of adaptation, however, allows the body’s rhythm to change itself according to time zone and seasonal sleep cycles.  When SCN neurons were observed individually, single SCN cells were found to eventually lose their rhythm.  This observation led to the conclusion that “the network structure of the SCN is important for stabilizing these sloppy intrinsic rhythms (6).” Chemical isolation of these neurons also proved that they were not specialized for certain tasks as repeated chemical isolation had different results among the same tested neurons.  This study demonstrated that the accuracy of Forger’s data could be improved.  Combined with Webb’s study, Forger’s work could glean even better information about the human body’s circadian rhythm.

The mechanics of these recent discoveries are exciting for biological scientists.  Nevertheless, what do they mean for the not-so-scientific, average man?  Forger’s research, as well as that of Webb’s, “is an essential step toward correcting sleep problems like insomnia” (4) as studying how the SCN function could result in a potential solution to the problem of damaged SCN, which leads to sleep disorders like insomnia.  Discoveries like these could also lead to a better understanding of diseases influenced by these systems, such as cancer.  In the case of cancer, melatonin (the chemical that controls the sleep cycle) has been found to inhibit growth of a number of cancerous cell lines and tumors.  (7)  By improving their understanding of how melatonin works in SCN cells, researchers can more closely understand melatonin’s involvement with the biological systems of cancer.  Circadian rhythms have also been found to influence metabolism, blood sugar control and aging. Unfortunately, the novelty of these discoveries makes it difficult for scientists to derive the exact implications of these experiments. It is not easy to begin to make concrete conclusions about studies in an area of research which has just begun to gain momentum.  However, one can only hope that these discoveries lead to a solution for those long, sleepless nights.

References
1. National Sleep Foundation, One-Third of Americans Lose Sleep over Economy (Press Release, March 2009; http://www.sleepfoundation.org/article/press-release/one-third-americans-lose-sleep-over-economy).
2. P.R. Carney, R.B. Berry, J.D. Geyer, in Clinical Sleep Disorders, A.M. Sydor, S. Scheidt, Eds. (Lippincott Williams & Wilkins, Philadelphia, 2005), pp. 88-89.
3. M. Barinaga Science 288 (5468), 943a; published online 12 May 2000 (10.1126/science.288.5468.943a).
4. Eur. J. Biology & Nature (8 October 2009), in press (available at http://esciencenews.com/articles/2009/10/08/u.m.discovery.about.biological.clocks.overturns.long.helh.theory).
5. Eur. J. Biology & Nature (8 October 2009), in press (available at http://esciencenews.com/articles/2009/10/08/scientists.reveal.new.pattern.our.daily.clock).
6. Eur. J. Biology & Nature (9 September 2009), in press (available at http://esciencenews.com/articles/2009/09/09/individual.cells.isolated.biological.clock.can.keep.daily.time.are.unreliable).
7. V. Srinivasan, D.W. Spence, S.R. Pandi-Perumal, I. Trakht, D.P. Cardinali, “Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms,” Integrative Cancer Therapies. 7, No. 3, 189-203 (2008).

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