Disruption in an astronaut’s circadian rhythm decreases performance levels during extended space missions. Using animal models, Dr. Michael Menaker is exploring ways to adapt the circadian rhythm to space by manipulating “constant” conditions, such as meal timing, melatonin administration, exercise, and short pulses of complete darkness. If these methods prove effective, they can be applied easily to maximize human performance in space.
Overview
A Model of Circadian Disruption in the Space Environment
Principal Investigator:
Michael Menaker, Ph.D.
Organization:
University of Virginia
Technical Summary
Original Aims
- To simulate the circadian "dysphasia" that might be produced by the arrhythmic environment of a space vehicle, we will measure the effects of long-term exposure to constant light on phase relationships among circadian oscillators in the brain and peripheral structures of transgenic rats carrying a luciferase reporter construct (Per1-luc).
- We will measure the effects of repeatedly shifting schedules of light cycle exposure, food availability, and work (i.e., forced running) in producing circadian dysphasia in our transgenic rats.
- We will attempt to restore normal circadian synchrony by using short, periodic applications of bright light, complete darkness, and melatonin, and by regularizing feeding and work schedules.
- We will develop a method of simultaneously measuring multiple circadian oscillators in awake, behaving animals using light guides chronically implanted in several brain areas and in peripheral organs and tissues.
Key Findings
Using luciferase technology we were able to study and measure the rhythmic expression of the mPer1-luc transgene (time of highest peak of bioluminescence) in samples of central and peripheral circadian oscillators in vitro taken from explanted tissues of pinealectomized and sham-operated rats exposed to different lighting conditions and after a rapid phase shift of the light-dark cycle. We tested the hypothesis that melatonin secreted by the pineal gland into the circulation functions as a signal to coordinate the distribution of phases of peripheral oscillators, thus defining the internal temporal order. If melatonin is in fact affecting the phase distribution among different oscillators, we expect that after pinealectomy, oscillators in different tissues will drift apart from their respective phases in sham-operated or intact animals. Furthermore, phase shifts of the light-dark cycle would reveal what tissues (if any) are most dependent on melatonin for phase shifting.
Impact
Our results suggest that pineal melatonin has only a minor role in the adjustment of phases among central and specific peripheral oscillators. Hence, pineal melatonin does not seem to be an important signal for the maintenance of internal synchrony, and our results do not support the use of melatonin as a countermeasure for this aspect of space travel-induced dysphasia.
Research Plan for Coming Year
Recently we have repeated and extended an important, but neglected, 20-year old observation from the Honma laboratory in Sapporo. They found that SCN-lesioned, arrhythmic rats regained rhythmicity when given methamphetamine chronically in their drinking water. We have replicated their observations in mice, providing the opportunity to investigate the molecular mechanisms underlying this phenomenon using genetic tools available only in mice. Although this was not proposed in our initial grant, we are pursuing it aggressively because the data imply the existence of a brain oscillator, distinct from the SCN which may well be involved in pathological responses to the space environment. We have applied for separate funding from the NIMH to further support this new work.
Earth Applications
There are several potential Earth-based applications of our work that could generally improve human health.
- Methylphenidate and, more importantly, rigid feeding schedules may be useful for temporarily stabilizing circadian phase in the face of disrupting environments.
- Sympathetic nervous system agonists and antagonists of several kinds may be used to modify phase relationships among some peripheral circadian oscillators and thus improve the outcomes of chronic therapeutic treatments of cancer and other chronic conditions (i.e., high blood pressure and irregular heart beat).
- The reproductive cycles in particular their circadian components of women engaged in activities with disruptive schedules may be regularized by carefully timed application of LH or FSH. Our data suggest that shift work schedules in which cycles are repeatedly delayed will be less damaging to the health of workers than those in which these cycles are repeatedly advanced.
This project's funding ended in 2004