A Model of Circadian Disruption in the Space Environment

We have developed a transgenic rat model that enables us to measure circadien rhythms of transcription of a "dock gene" (Perl) in the brain and in peripheral tissues. Using this model we have shown that Perl transcription is circadian in vitro preparations of suprachiasmatic nucleus (SCN), several other brain areas, liver, lung, muscle, and other peripheral organs. This demonstrates that each of these areas and organs contain circadian oscillators -- those in the SCN are self-sustained and persist far more than a month in vitro, while those in other areas damp out within one to six cycles once tissues containing them have been removed from the animal.

This data supports a hierarchical model of mammalian circadian organization, with the SCN as the dominant synchronizer of rhythms in other brain areas and in the periphery. In addition, our new rat model provides unique opportunities to test the effects of "abnormal" environments, such as those that will be encountered in space travel, on organization of the mammalian circadian system.

We propose to evaluate the effects of "constant" conditions and of shift-work schedules on both the maintenance of circadian rhythmicity in central and peripheral structures, and on temporal synchrony among them (specific aims 1 and 2). Our preliminary data indicates that under these conditions, some circadian rhythms will be abolished, others will be abnormally phased (i.e., will peak at the "wrong" Lime relative to the light cycle and/or rhythms in other tissues), while yet others (in particular, the SCN) may be unaffected. We have called the resulting abnormal circadian organization "dysphasia," and hypothesize that it is responsible for the malaise and pertiunuance decrements seen in jet lag and shift-work syndrome. We believe that to the degree possible, it should be avoided in space travel.

In a final set of experiments (specific amis 3 and 4), we will attempt to ameliorate or prevent dysphasia by manipulating meal timing, melatonin administration, forced exercise, and short pulses of complete darkness. We have focused on these interventions because they could be applied with relative ease and saftey to humans in space, and there is good reason to expect that they would be effective.