The effects of gravity on the circadian timing system

The physiological system responsible for the temporal coordination of an organism is the circadian timing system (CTS). This system provides two forms of temporal coordination. First, the CTS provides for synchronization of the organism with the 24 hour period of the external environment. This synchronization of the organism with the environment is termed entrainment. Second, this system also provides for internal coordination of the various physiological, behavioral, and biochemical events within the organism. When either of these two temporal relationships are disturbed, various dysfunctions can be manifest within the organism. Homeostatic capacity of other physiological systems may be reduced. Performance is decreased and sleep disorders, mental health impairment (e.g., depression), jet lag syndrome, and shift work maladaptation frequently occur. Over the last several years, several studies have evaluated the potential influence of gravity on this physiological control system by examining changes in rhythmic characteristics of organisms exposed to altered gravitational environments. The altered gravitational environments have included the microgravity of spaceflight as well as hyperdynamic fields produced via centrifugation.     

The circadian timing system and reproduction in mammals.

Circadian systems in a wide variety of organisms all appear to include three basic components: 1) biological oscillators that maintain a self-sustained circadian periodicity in the absence of environmental time cues; 2) input pathways that convey environmental information, especially light cues, that can entrain the circadian oscillations to local time; and 3) output pathways that drive overt circadian rhythms, such as the rhythms of locomotor activity and a variety of endocrine rhythms. In mammals, the circadian system is employed in the regulation of reproductive physiology and behavior in two very important ways. 1) In some species, there is a strong circadian component in the timing of ovulation and reproductive behavior, ensuring that these events will occur at a time when the animal is most likely to encounter a potential mate. 2) Many mammals exhibit seasonal reproductive rhythms that are largely under photoperiod regulation; in these species, the circadian system and the pineal gland are crucial components of the mechanism that is used to measure day length. The rhythm of pineal melatonin secretion is driven by a neural pathway that includes the circadian oscillator(s) in the suprachiasmatic nuclei. Melatonin is secreted at night in all mammals, and the duration of each nocturnal episode of melatonin secretion is inversely related to day length. The pineal melatonin rhythm appears to serve as an internal signal that represents day length and that is capable of regulating a variety of seasonal variations in physiology and behavior.     

Plasticity of the intrinsic period of the human circadian timing system

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2)) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.     

Computational modeling of synchronization process of the circadian timing system of mammals

This paper presents a model for the circadian temporization system of mammals which associates the synchronization dynamics of coupling oscillators to a set of equations able to reproduce the synaptic characteristics of somatodendritic membrane of neurons. The circadian timing system is organized in a way to receive information from the external and internal environments, and its function is the timing organization of physiological and behavioral processes in a circadian pattern. Circadian timing system in mammals is constituted by a group of structures which includes the suprachiasmatic nucleus, the intergeniculate leaflet and the pineal gland. In suprachiasmatic nucleus are found neuron groups working as a biological pacemaker—the so-called biological master clock. By means of numerical simulations using the Kuramoto model, we simulated the dynamics behavior of the biological pacemaker. For this we used a set of 1,000 coupled oscillators with long-range coupling, which were distributed on a 10 × 10 × 10 spherical lattice, and a new method to estimate the order parameter, which characterizes the degree of synchronization of oscillator system. Our model has been able to produce frequency responses in accordance with physiological patterns, and to reproduce two fundamental characteristics of biological rhythms: the endogenous generation and synchronization to the light–dark cycle.     

Temporal dynamics of late-night photic stimulation of the human circadian timing system

The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift. A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with approximately 100 lux evoking half of the effects observed with light 10 times as bright.     

Acute exposure to 2G phase shifts the rat circadian timing system

The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cues (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination but exhibit a "free-running" condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral physiological systems that express these circadian parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.     

The mammalian circadian timing system: from gene expression to physiology

Many physiological processes in organisms from bacteria to man are rhythmic, and some of these are controlled by self-sustained oscillators that persist in the absence of external time cues. Circadian clocks are perhaps the best characterized biological oscillators and they exist in virtually all light-sensitive organisms. In mammals, they influence nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrinology, body temperature, renal activity, physiology of the gastro-intestinal tract, and hepatic metabolism. The master pacemaker is located in the suprachiasmatic nuclei, two small groups of neurons in the ventral part of the hypothalamus. However, most peripheral body cells contain self-sustained circadian oscillators with a molecular makeup similar to that of SCN (suprachiasmatic nucleus) neurons. This organization implies that the SCN must synchronize countless subsidiary oscillators in peripheral tissues, in order to coordinate cyclic physiology. In this review, we will discuss some recent studies on the structure and putative functions of the mammalian circadian timing system, but we will also point out some apparent inconsistencies in the currently publicized model for rhythm generation.     

Ecdysteroids influence the circadian system timing ecdysis in the insectRhodnius prolixus (Hemiptera)

Summary 20-hydroxyecdysone (20HE) injections induced transient delays in the time of ecdysis inRhodnius prolixus reared in L/D cycles. Sustained phase delays in the ecdysis rhythm were revealed by transfer to constant dark during the scotophase following 20HE injection. The magnitude of the phase delays depended on the time in the L/D cycle at which 20HE was injected with major delays occurring at times when the endogenous titre is declining. Therefore the increases and decreases in the endogenous titre which are themselves timed in a circadian fashion may be involved in phase setting the ecdysis rhythm to the environmental cycle. Populations maintained in LL which are arrhythmic with respect to both ecdysteroid titres and ecdysis, can be induced to display gated ecdysis by injection of either 20HE or antiserum to ecdysteroids. Multiple injections of 20HE or antiserum are capable of inducing an ecdysis rhythm whose period (22.3 h) and gate location are very similar to that produced by altering the environmental cycle. Therefore manipulations of the endogenous titre of ecdysteroids can mimic the effects of L/D cycles on the timing of ecdysis. Ecdysis inRhodnius may therefore be timed at least partially as a result of circadian timing of the ecdysteroid titre.Abbreviations AZT Arbitrary Zeitgeber Time - DD constant darkness - LL constant light - L/D 24 h light dark cycle - 12L/12D 12 h of light 12 h of dark - 20HE 20-hydroxyecdysone     

Pseudorabies virus recombinants expressing functional virulence determinants gE and gI from bovine herpesvirus 1.1.

In the Alphaherpesvirinae subfamily, the gE and gI genes are conserved and encode membrane glycoproteins required for efficient pathogenesis (virulence). The molecular mechanism(s) responsible is not well understood, but the existence of similar phenotypes of gE and gI mutations in diverse Alphaherpesvirinae implies conservation of function(s). In this report, we describe construction of pseudorabies virus (PRV) recombinants that efficiently express the bovine herpesvirus 1 (BHV-1) membrane proteins gI and gE at the PRV gG locus. Each BHV-1 gene was cloned in a PRV mutant lacking both the PRV gI and gE coding sequences. All recombinant viruses expressed the BHV-1 proteins at levels similar to or greater than that observed after infection with parental BHV-1, and there were no observable differences in processing or ability to form gE-gI oligomers. The important observation resulting from this report is that the BHV-1 gE and gI proteins functioned together to complement the virulence defect of PRV lacking its own gE and gI genes in a rodent model, despite being derived from a highly restricted host range virus with a different pathogenic profile.     

Perfect timing: epigenetic regulation of the circadian clock

In mammals, higher order chromatin structures are critical for downsizing the genome (packaging) so that the nucleus can be small. The adjustable density of chromatin also regulates gene expression, thus this post-genetic molecular mechanism is one of the routes by which phenotype is shaped. Phenotypes that arise without a concomitant mutation of the underlying genome are termed epigenetic phenomena. Here we discuss epigenetic phenomena from histone and DNA modification as it pertains to the dynamic regulatory processes of the circadian clock. Epigenetic phenomena certainly explain some regulatory aspects of the mammalian circadian oscillator.     

Extraocular phototransduction and circadian timing systems in vertebrates

It is widely accepted that, for organisms with eyes, the daily regulation of circadian rhythms is made possible by light transduction through those organs. Yet, it has been demonstrated repeatedly in recent years that ocular light receptors that mediate vision, at least in mammals, are not the same photoreceptors involved in circadian regulation. Moreover, it has been recognized for many years that circadian regulation can occur in organisms without eyes. In fact, extraocular circadian phototransduction (EOCP) appears to be a phylogenetic rule for the vast majority of species. EOCP has been reported in every nonmammalian species studied to date. In mammals, however, the story is very different. This paper presents findings from studies that have examined specifically the capacity for EOCP in vertebrate species. In addition, the literature addressing noncircadian aspects of extraocular phototransduction is briefly discussed. Finally, possible mechanisms underlying EOCP are discussed, as are some of the implications of the presence, or absence, of EOCP across phylogeny. (Chronobiology International, 18(2), 137-172, 2001)     

Precision of circadian wake and activity onset timing in the mouse

In each circadian cycle, a mouse begins its major activity period with discrete wake onset and activity onset events. The precision with which these events are timed in constant darkness was analyzed using the approach outlined by Pittendrigh and Daan (1976). Negative serial correlations of observed circadian period values (mean r1 = -0.471 for wake data, -0.409 for activity data) imply that deviations in period tend to be compensated by opposite deviations in the following cycle. As a result, precision of the circadian pacemaker must be better than that of observed rhythms. Standard deviation of the pacemaker period sigma(tau) was estimated at 5.1 min. Some individual data series had estimates s(tau) = 0, implying a nearly perfect pacemaker. Previous speculation was that wake onset would be under more direct pacemaker control than activity onset, and would therefore be timed more precisely (Pittendrigh and Daan 1976; Richardson et al. 1985). Contrary to this prediction, intervals between successive wake onsets exhibited significantly greater variance than intervals between successive activity onsets. Two possible interpretations of this finding were proposed.