SLEEP, MELATONIN AND THE AGING CIRCADIAN CLOCK

The central goal of this new Program Project is to understand the role of
the hormone melatonin on the brain structures [especially the
suprachiamatic nuclei (SCN) in the hypothalamus] that generate the sleep-
alertness rhythm (as well as other circadian rhythms); and to understand
the significance of aging on this system. This understanding will be
accelerated by an alliance of basic and clinical scientists who will be
working closely together on this goal. This program will accomplish the
following aims: 1) Melatonin will be administered to elderly human
subjects at different times of the day, in order to measure phase-shifts in
the timing of the endogenous melatonin rhythm, and to thereby construct a
phase response curve (PRC). this PRC will be compared to the PRC obtained
in another project for younger subjects, and will be interpreted as a
measure of the responsiveness of the circadian system in elderly people.
2) Melatonin administration will also be tested as a means of increasing
the quality and quantity of sleep in elderly subjects. 3) Melatonin
administration will be tested as a means of shifting the circadian phase in
aging subjects whose rhythms are desynchronized because of shift work. 4)
Molecular clones encoding functional melatonin receptors will be isolated
and characterized which will elucidate the molecular and cellular actions
of melatonin. 5) The electrical activity and response of individual cells
within the SCN will be studied with the aim of understanding the
fundamental mechanisms by which this structure generates a 24-hour rhythm
and responds to melatonin. Because of the close collaboration fostered by this program, insights
gained at the basic level can be quickly and efficiently tested in human
subjects. In turn, the behavioral and physiological knowledge gained from
human studies can guide the search for basic mechanisms. The knowledge
gained by this research program will provide the basis for the rational
assessment and intervention of circadian abnormalities of the sleep/wake
cycle in elderly patients, thus promoting consolidated, restorative sleep,
at the preferred time of the night (or day).