Mar 2, 2008

Your internal body clock: the suprachiasmatic nucleus (SCN)

Although studies of unicellular organisms point to the cellular nature of the system generating circadian rhythms, the circadian pacemaker in higher organisms is located in cells of specific structures of the organism. These structures include certain regions of the brain (i.e., the optic and cerebral lobes) in insects; the eyes in certain invertebrates and vertebrates; and the pineal gland, which is located within the brain, in nonmammalian vertebrates.

In mammals, the circadian clock resides in two clusters of nerve cells called the suprachiasmatic nuclei (SCN), which are located in a region at the base of the brain called the anterior hypothalamus.

The role of the SCN was demonstrated by the landmark discovery in the early 1970s that by damaging (i.e., lesioning) the SCN in rats, researchers could disrupt and abolish endocrine and behavioral circadian rhythms (Klein et al. 1991). Furthermore, by transplanting the SCN from other animals into the animals with the lesioned SCN, investigators could restore some of the circadian rhythms.

Finally, the SCN’s role as a master pacemaker regulating other rhythmic systems was confirmed by similar studies in hamsters, which demonstrated that the restored rhythms exhibited the clock properties (i.e., the period, or phase, of the rhythm) of the donor rather than of the host (Ralph et al. 1990). The discovery that the SCN is the site of primary regulation of circadian rhythmicity in mammals gave researchers a focal point for their research: if one wanted to understand 24-hour timekeeping, one needed to study the clock in the SCN.

Recently, however, researchers have been surprised to find that circadian rhythms could persist in isolated lungs, livers, and other tissues grown in a culture dish (i.e., in vitro) that were not under the control of the SCN (Yamazaki et al. 2000). These observations indicate that most cells and tissues of the body may be capable of modulating their activity on a circadian basis.
Such findings do not, however, diminish the central role played by the SCN as the master circadian pacemaker that some-how coordinates the entire 24-hour temporal organization of cells, tissues, and the whole organism.

The physiological mechanisms underlying this coordination include signals emitted by the SCN that act on other nerve cells (i.e., neural signals) or which are also distributed through the blood to other organs (i.e., neurohormonal signals). To date, however, the characteristics of the circadian signal itself-that is, the specific manner in which the SCN “talks” to the rest of the body-remain unknown (see Stokkan et al. 2001).

Although the effects of SCN lesions on numerous rhythms have been elucidated, their effects on sleep are less clear. Thus, SCN lesions clearly disrupt the consolidation and pattern of sleep in rats but have only minimal effects on the animals’ amount of sleep or sleep need (Mistlberger et al. 1987). For this and other reasons, researchers have postulated that sleep is subject to two essentially independent control mechanisms: (1) the circadian clock that modulates the propensity for sleep and (2) a homeostatic control that reflects the duration of prior waking (i.e., “sleep debt”).

Recently, however, studies in squirrel monkeys found that SCN lesions can affect the amount of sleep. Moreover, sleep studies in mice carrying changes (i.e., mutations) in two of the genes influencing circadian cycles (i.e., the DBP and Clock genes) indicated that these mutations resulted in changes in sleep regulation (Naylor et al. 2000; Franken et al. 2000).

Both of these observations raise the intriguing possibility that the homeostatic and circadian controls may be more interrelated than researchers previously thought.

By Martha Hotz Vitaterna, Ph.D., Joseph S. Takahashi, Ph.D., and Fred W. Turek, Ph.D.
MARTHA HOTZ VITATERNA, PH.D., is a senior research associate in the Center for Functional Genomics, Northwestern University, Evanston, Illinois. JOSEPH S. TAKAHASHI, PH.D., is the director of the Center for Functional Genomics, the Walter and Mary E. Glass Professor in the Department of Neurobiology and Physiology, and an investigator at the Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois. FRED W. TUREK, PH.D., is the director of the Center for Sleep and Circadian Biology and is the Charles T. and Emma H. Morrison Professor in the Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois.

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