SECTION 1 - BASIC SLEEP SCIENCE

Circadian Biology

Background

Circadian oscillators are critically involved in the regulation of the sleep/wakefulness cycles, although the relationship is complex and not fully understood. It is generally recognized that the sleep/wakefulness rhythm is not driven directly by the circadian clock, but rather emerges from an interaction of the circadian clock located within the suprachiasmatic nucleus (SCN), and a distinct sleep-wake homeostatic process (e.g., the "sleep homeostat") in which the drive or need for sleep depends upon the prior amount of wakefulness and sleep. Sleep disorders may arise from dysfunction at several levels within these two timing systems. Alterations in the circadian pacemaker within the SCN, changes in the sleep homeostat, and alterations in the coupling between the two timing systems may each be causal in sleep disturbances. A complete understanding of the origins of normal and abnormal sleep will require a detailed understanding of both the circadian and sleep/wakefulness systems.

Progress In The Last 5 Years

- Identification of the first mammalian clock genes: Within the past 5 years 8 "clock genes" have been identified that play a critical role in mammalian circadian timing. A recent study indicates that alterations in the hPer2 gene are associated with advanced sleep phase syndrome. In addition, mutations of the murine Clock gene affect both sleep duration and the response to sleep loss, indicating that some genes may be involved in both the timing and pressure to sleep.

- Confirmation of the multi-oscillatory, distributed nature of the mammalian timing system: Dynamic measurements of molecular rhythms from several clock genes reveal that many organs and non-SCN regions of the brain express circadian rhythms, although not as robust as the rhythm generated by the SCN. These observations raise issues about the role of non-SCN rhythm generators in the control of the sleep/wakefulness cycle and the development of sleep disorders.

- Discovery of temporal complexity within the SCN: Recent experiments reveal regional specialization in the capacity to express circadian rhythms. It is evident that not all SCN neurons enjoy the same phase relationship to one another. Molecular rhythms of the right and left SCN appear out of phase in behaviorally split animals and phase differences among SCN neurons may be responsible for encoding day length information.

- Discovery that circadian photoreception is functionally and anatomically separate from vision and that this non-visual system may affect many physiological and behavioral systems: These findings are important because sleep/wake rhythms are regulated by photoreception via the SCN and the sleep/wakefulness cycle can influence photoreception (e.g., eye closure during sleep). These photoreceptors may be linked directly to sleep centers in the brain since there are retinal afferents of unknown function that project directly to these centers.

- Discovery of new neurotransmitter systems and anatomical areas of the brain, especially the hypothalamus, and in particular discovery of the orexins/hypocretins in the regulation of REM sleep: These anatomical and neurochemical targets are linked to the SCN and provide new avenues for studying the interactions of the circadian clock and sleep-waking timing systems.

- Discovery that chronic partial sleep loss for as little as one week can lead to metabolic and endocrine changes that are precursors for specific disease states (e.g., obesity and diabetes) and are also relevant to aging: Decreased total sleep time is often associated with circadian dysfunction either on a voluntary basis (e.g., shift work) or involuntary basis (e.g., as in aging), making it imperative to determine the importance of circadian factors that lead to decreased sleep and the health consequences associated with chronic sleep loss.

- Discovery that the rest phase of the rest-activity cycle of the fruit fly shares many behavioral and pharmacological features associated with sleep: This should allow this model organism to be used to further explore the molecular and genetic basis of sleep and the adverse effects of sleep deprivation.

Research Recommendations

- The neurobiological basis of the two-process sleep system. Recognition of the importance of these two separate timing processes controlling sleep rhythmicity will continue to provide an important conceptual framework for the dissection of altered sleep regulation. The anatomical, physiological and functional links between the two systems are virtually unknown. The search for the neurobiological basis of these two processes and their interaction should remain at the center of basic research in this area. A more complete characterization of the contribution of these two processes to altered sleep timing and quality, in particular with development and aging, is important.

- Circadian physiology of sleep disorders. The pathophysiology of certain disorders of the timing of sleep remains to be fully characterized and understood at a fundamental level. Circadian desynchrony is considered to be at the core of certain disorders that involve both insomnia and sleepiness (e.g., delayed sleep phase syndrome; shift work sleep disorder). Given the number of people affected by these disorders and the behavioral debilitation, it is important to determine whether any of the key circadian parameters (e.g., free-running period (tau), PRC, light sensitivity, internal coupling between sleep and other circadian-mediated physiology, etc.) are altered in these disorders. It will also be important to search for linkages between circadian rhythms and sleep disorders not normally associated with circadian timing (e.g., Restless Legs Syndrome).

- The availability of clock gene mutations in mammals will allow study of the effects of alterations of the circadian pacemaker on the sleep/wakefulness rhythm. In addition, these genes may have effects on sleep that are independent of the SCN. It will be important to determine how these genes act to regulate sleep independent of the central pacemaker, and. to assess the effects of circadian period, phase and amplitude on the sleep/wakefulness rhythm.

- Although the free-running period (tau) of the human circadian rhythm may not change during aging, animal studies suggest an impact on other circadian parameters (e.g., amplitude). It will be important to explore the effects of aging on central and peripheral circadian generators and how age-related changes in circadian function affect sleep.

- How circadian dysregulation and sleep loss interact to affect health is an important but poorly understood topic. This issue is of particular importance to the aged and to disadvantaged populations. Multiple jobs and unusual work cycles can lead to circadian disruption. It will also be important to understand the long-term effects of chronic sleep loss in adolescents. Good model systems and more sophisticated long-term data collection will be essential.

- In vivo measurement of circadian phase. There is a need to develop methodology for non-invasive measurement of human circadian phase. This may require the identification of new markers and/or the development of novel detection systems.

- Quantitative modeling of a mammalian circadian clock. The molecular processes and interactions that appear to generate rhythmicity will need to be described in a mathematically rigorous fashion. The central clock mechanism has grown in complexity with an attendant loss of conceptual clarity. Modeling may allow for a better focus on critical processes.

- Although it is clear that there are significant sleep problems associated with adjustment to shift work and transmeridian flight, our understanding about entrainment kinetics is very limited. In particular, little is known about entrainment kinetics in older individuals who have more difficulty in maintaining stably entrained biological rhythms. Recent research indicating that different circadian rhythm generators within the brain and other organs reset with different kinetics suggests that the physiology of internal and external synchronization is important. Molecular and neurophysiological tools are now available in several animal model systems to address these problems.

- Animal research indicates that circadian photoreception enjoys distinct photoreceptors within the retina and specialized neural pathways. A full functional and molecular characterization of this system is required in humans.