Principal Investigator:	Michael Menaker, Ph.D.
Organization:	University of Virginia
Project Ended:	2008

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 and lighting. His research also looks to isolate and identify the four likely signals responsible for the disruption of circadian rhythms: melatonin, adrenal steroids, sympathetic neural input (epinephrine and norepinephrine) and parasympathetic input (acetylcholine). If these methods prove effective, they can be applied to maximize human performance in space.

Principal Investigator:	Michael Menaker, Ph.D.
Organization:	University of Virginia
Project Ended:	2008

Original Aims

1. Using rhythms of gene expression reported by a luciferase transgene, we will identify the signals linking brain and peripheral oscillators.
2. Evaluate potential countermeasures by exposing our experimental animals to conditions that disrupt the normal circadian phase map and by then determining if the potential countermeasures are able to restore it rapidly.
3. Investigate the effects of chronic low-dose methamphetamine in synchronizing disrupted rhythms and evaluate related drugs as potential countermeasures.

Key Findings
We have extended our studies of the methamphetamine-sensitive circadian oscillator (MASCO) and have discovered a sex difference in the effect of methamphetamine on C3H mice, i.e., females are less responsive than males. We have now demonstrated that gonadectomy does not alter the circadian response of either males or females to methamphetamine, and thus sex hormones are unlikely to explain the sex difference. In addition, we have been screening circadian mutant mice to determine if there is a role for canonical clock genes in the effect of methamphetamine on free-running period length. All of the arrhythmic mutant mice screened to date have become rhythmic in the presence of methamphetamine. This demonstrates that MASCO is indeed a distinct brain oscillator, which may be involved in the pathological responses of the circadian system to the space environment. We have also extended our study of the phase synchronizing effect of methamphetamine on circadian oscillators. We previously demonstrated that ablation of the suprachiasmatic nucleus (SCN) results in phase desynchrony between internal oscillators and that methamphetamine administration is capable of restoring coherent phase relationships between peripheral tissues. In the past year, we have run another group of animals confirming and elaborating on our prior experiments. We have now included two additional tissues (lung and pituitary) in our analysis and compared the effect of methamphetamine to that of food restriction. The results demonstrate that both methamphetamine and food restriction can restore phase synchrony, in at least some tissues, following SCN lesion. This is particularly exciting because programming meal times is a noninvasive and potentially beneficial way to treat circadian disorganization produced by the space environment.

We have finished our studies of the phase-controlling signals to two internal organs, the ovary and the submaxillary gland. One paper has been published from this data and another is in preparation. To summarize these findings:

1. The ovary responds to pituitary hormones and does not require neural signals;
2. The salivary gland responds to both neural signals and to feeding time, if and only if the neural inputs are cut. This variety of responses suggest that internal circadian organization is normally maintained by many different signals that are specific to particular organs or groups of organs and may be hierarchically organized. Understanding and eventually controlling them will be an important but difficult undertaking.

Impact of Findings
Our project is intended to provide some of the basic data that will be needed to minimize the effects of disrupting the circadian rhythms of astronauts and ground-based support personnel during their missions. Such disruption is an inevitable result of the work schedules that these men and women are required to follow. Disruption of circadian organization, which includes but is not limited to sleep deprivation, has repeatedly been shown to affect alertness, cognition and performance on a variety of tasks. In order to minimize these effects, we have to understand the organization of the system that is being affected. In particular, we have to identify general signals such as meal timing that are capable of maintaining internal synchrony with minimal associated side effects.

Principal Investigator:	Michael Menaker, Ph.D.
Organization:	University of Virginia
Project Ended:	2008

There are several potential Earth-based applications of our work that could generally improve human health:

1. Methylphenidate and, more importantly, rigid feeding schedules may be useful for temporarily stabilizing circadian phase in the face of disrupting environments.
2. 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).
3. The reproductive cycles, in particular their circadian components, of women engaged in activities with disruptive schedules may be regularized by carefully timed application of luteinizing hormone or follicle-stimulating hormone.
4. 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.