Aging and biological rhythms in primates

All living organisms exhibit rhythmic activities in a wide variety of endocrine and behavioural parameters. These biological rhythms are endogenously generated by a circadian clock, and they are entrained by cyclic variations of environmental factors called synchronizers. Aging is associated with changes in amplitude and temporal organization of many daily and seasonal rhythms. In humans, daily rhythms of sleep, thermoregulation and hormonal secretion are severely altered with aging. Except in humans, studies on primates are scarce. However, age-related effects on biological rhythms are relatively consistent among primate species studied to date, including humans. Therefore, non human primates are of valuable use for such investigations. Most studies have been performed on the Rhesus macaque (longevity 35-40 years) and on the gray mouse lemur (longevity 10-12 years). Like in humans, the rest-activity rhythm becomes fragmented in aged primates, and shows an increased activity during the resting period. Aging induces a decrease in amplitude of the body temperature rhythm and an increase in energy consumption. Various hormonal secretions exhibit a decrease with aging, but the rhythmic components of these declines have not always been depicted. Moreover, changes (amplitude or phase) in daily variations depended of the hormonal secretion tested. Taken together, these results suggest that the biological clock in the brain would be a primary target of aging. The main central clock is located in the suprachiasmatic nucleus of the hypothalamus whose endogenous oscillations are entrained by light. In this brain structure, cellular function and sensitivity to light show drastic changes with age in the mouse lemur. The precise knowledge of age-related alterations of biological rhythms in primates can have important consequences on the development of new treatments to maintain or restore biological rhythmicity in the elderly.     

Drosophila Free-Running Rhythms Require Intercellular Communication

Robust self-sustained oscillations are a ubiquitous characteristic of circadian rhythms. These include Drosophila locomotor activity rhythms, which persist for weeks in constant darkness (DD). Yet the molecular oscillations that underlie circadian rhythms damp rapidly in many Drosophila tissues. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms that underlie the differences between damped and self-sustaining oscillations remain largely unknown. A small cluster of neurons in adult Drosophila brain, the ventral lateral neurons (LN_vs), is essential for self-sustained behavioral rhythms and has been proposed to be the primary pacemaker for locomotor activity rhythms. With an LN_v-specific driver, we restricted functional clocks to these neurons and showed that they are not sufficient to drive circadian locomotor activity rhythms. Also contrary to expectation, we found that all brain clock neurons manifest robust circadian oscillations of timeless and cryptochrome RNA for many days in DD. This persistent molecular rhythm requires pigment-dispersing factor (PDF), an LN_v-specific neuropeptide, because the molecular oscillations are gradually lost when Pdf⁰¹ mutant flies are exposed to free-running conditions. This observation precisely parallels the previously reported effect on behavioral rhythms of the Pdf⁰¹ mutant. PDF is likely to affect some clock neurons directly, since the peptide appears to bind to the surface of many clock neurons, including the LN_vs themselves. We showed that the brain circadian clock in Drosophila is clearly distinguishable from the eyes and other rapidly damping peripheral tissues, as it sustains robust molecular oscillations in DD. At the same time, different clock neurons are likely to work cooperatively within the brain, because the LN_vs alone are insufficient to support the circadian program. Based on the damping results with Pdf⁰¹ mutant flies, we propose that LN_vs, and specifically the PDF neuropeptide that it synthesizes, are important in coordinating a circadian cellular network within the brain. The cooperative function of this network appears to be necessary for maintaining robust molecular oscillations in DD and is the basis of sustained circadian locomotor activity rhythms.     

Drosophila free-running rhythms require intercellular communication

Robust self-sustained oscillations are a ubiquitous characteristic of circadian rhythms. These include Drosophila locomotor activity rhythms, which persist for weeks in constant darkness (DD). Yet the molecular oscillations that underlie circadian rhythms damp rapidly in many Drosophila tissues. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms that underlie the differences between damped and self-sustaining oscillations remain largely unknown. A small cluster of neurons in adult Drosophila brain, the ventral lateral neurons (LN_vs), is essential for self-sustained behavioral rhythms and has been proposed to be the primary pacemaker for locomotor activity rhythms. With an LN_v-specific driver, we restricted functional clocks to these neurons and showed that they are not sufficient to drive circadian locomotor activity rhythms. Also contrary to expectation, we found that all brain clock neurons manifest robust circadian oscillations of timeless and cryptochrome RNA for many days in DD. This persistent molecular rhythm requires pigment-dispersing factor (PDF), an LN_v-specific neuropeptide, because the molecular oscillations are gradually lost when Pdf⁰¹ mutant flies are exposed to free-running conditions. This observation precisely parallels the previously reported effect on behavioral rhythms of the Pdf⁰¹ mutant. PDF is likely to affect some clock neurons directly, since the peptide appears to bind to the surface of many clock neurons, including the LN_vs themselves. We showed that the brain circadian clock in Drosophila is clearly distinguishable from the eyes and other rapidly damping peripheral tissues, as it sustains robust molecular oscillations in DD. At the same time, different clock neurons are likely to work cooperatively within the brain, because the LN_vs alone are insufficient to support the circadian program. Based on the damping results with Pdf⁰¹ mutant flies, we propose that LN_vs, and specifically the PDF neuropeptide that it synthesizes, are important in coordinating a circadian cellular network within the brain. The cooperative function of this network appears to be necessary for maintaining robust molecular oscillations in DD and is the basis of sustained circadian locomotor activity rhythms.     

Systems biology of cellular rhythms

Rhythms abound in biological systems, particularly at the cellular level where they originate from the feedback loops present in regulatory networks. Cellular rhythms can be investigated both by experimental and modeling approaches, and thus represent a prototypic field of research for systems biology. They have also become a major topic in synthetic biology. We review advances in the study of cellular rhythms of biochemical rather than electrical origin by considering a variety of oscillatory processes such as Ca++ oscillations, circadian rhythms, the segmentation clock, oscillations in p53 and NF-κB, synthetic oscillators, and the oscillatory dynamics of cyclin-dependent kinases driving the cell cycle. Finally we discuss the coupling between cellular rhythms and their robustness with respect to molecular noise.     

Further evidence that the circadian clock in Drosophila is a population of coupled ultradian oscillators

We hypothesize that ultradian oscillators are coupled to yield a composite circadian clock in Drosophila. In such a system, period would be a function of the tightness of coupling of these oscillators, increasing as coupling loosens. Ultradian oscillations would become apparent under weak coupling or in the absence of coupling. A new technique for calculating signal-to-noise ratio (SNR) for biological rhythms to characterize their precision has yielded support for this hypothesis. SNR of rhythms of the allelic series of mutations at the period (per) locus of Drosophila melanogaster were compared. Per(o) was the noisiest, grading through perL, per+, and pers, the least noisy. SNR decreases significantly with increasing period in pers, per+, and perL; per(o) typically has multiple ultradian oscillations and the lowest SNR. At least 70% of perL individuals also exhibit ultradian periodicities.     

Significance of biological rhythm study for human biometeorology

Summary The significance of biological rhythms for biometeorological research is reviewed, with special reference to man. Among external influences cosmic agents (mostly periodic) and meteorological agents (largely non-periodic)are discussed, as acting upon rhythmic of non-rhythmic biological transducers. It is stressed that there are two directions of relation: (1) from external agent to rhythm, synchronizing or modulating it; and (2) rhythms may sinply be a tool for studying meteorological non-periodic influences. Several characteristics of rhythms make them suited for the latter and special statistical methods, apart from the classical frequency analyses, may be fashioned for this.The discussion furthermore covers different types of synchronizers, their characteristics, pathways and possible modes of action;also the three main different types of external conditions such as constancy, normal conditions, and the experimental day with fixed light-dark changes. Tidal, lunar and seasonal rhythms are mentioned; also meteorotropic diseases, balneotherapy, and other rhythms in disease;spontaneous biological oscillators (with or without external correlates) and their control,multioscillator theories, linear and nonlinear interaction between oscillators; hidden and disturbed periodicities, transient damped oscillations, the ringing response,parametric control; phase and frequency synchronization, including translongitudinal travel and space conditions.     

Stochastic models for circadian rhythms: effect of molecular noise on periodic and chaotic behaviour

Circadian rhythms are endogenous oscillations that occur with a period close to 24 h in nearly all living organisms. These rhythms originate from the negative autoregulation of gene expression. Deterministic models based on such genetic regulatory processes account for the occurrence of circadian rhythms in constant environmental conditions (e.g., constant darkness), for entrainment of these rhythms by light-dark cycles, and for their phase-shifting by light pulses. When the numbers of protein and mRNA molecules involved in the oscillations are small, as may occur in cellular conditions, it becomes necessary to resort to stochastic simulations to assess the influence of molecular noise on circadian oscillations. We address the effect of molecular noise by considering the stochastic version of a deterministic model previously proposed for circadian oscillations of the PER and TIM proteins and their mRNAs in Drosophila. The model is based on repression of the per and tim genes by a complex between the PER and TIM proteins. Numerical simulations of the stochastic version of the model are performed by means of the Gillespie method. The predictions of the stochastic approach compare well with those of the deterministic model with respect both to sustained oscillations of the limit cycle type and to the influence of the proximity from a bifurcation point beyond which the system evolves to stable steady state. Stochastic simulations indicate that robust circadian oscillations can emerge at the cellular level even when the maximum numbers of mRNA and protein molecules involved in the oscillations are of the order of only a few tens or hundreds. The stochastic model also reproduces the evolution to a strange attractor in conditions where the deterministic PER-TIM model admits chaotic behaviour. The difference between periodic oscillations of the limit cycle type and aperiodic oscillations (i.e. chaos) persists in the presence of molecular noise, as shown by means of Poincaré sections. The progressive obliteration of periodicity observed as the number of molecules decreases can thus be distinguished from the aperiodicity originating from chaotic dynamics. As long as the numbers of molecules involved in the oscillations remain sufficiently large (of the order of a few tens or hundreds, or more), stochastic models therefore provide good agreement with the predictions of the deterministic model for circadian rhythms.     

Circadian rhythm entrainment in flies and mammals

Circadian rhythms are a fundamental adaptation of living cells to the daily and seasonal fluctuation in light and temperature. Circadian oscillations persist in constant conditions; however, they are also phase-adjusted (entrained) by day-night cycles. It is this entrainability that provides for the proper phasing of the program, to the sequence of external changes that it has evolved to exploit. Synchronization of circadian oscillators with the outside world is achieved because light, temperature, or other external temporal cues, have acute effects on the levels of one or more of the clock's components. The consequences are ripples through the interconnected molecular loops, leading to a stable phase realignment of the endogenous rhythm generator and the external conditions. This review summarized the evolving knowledge of the different types, modes, and molecular processes of entrainment in flies and mammals.     

Behavioral analysis of circadian rhythms: Entraining the circadian clock and determining the food-entrainable oscillator mechanism

Sleep and Biological Rhythms - Circadian rhythms are oscillations in behavior and physiological functions that are regulated by internal biological clocks. In mammals, the circadian rhythms can be...     

Seven-day human biological rhythms: An expedition in search of their origin,synchronization, functional advantage,adaptive value and clinical relevance

This fact-finding expedition explores the perspectives and knowledge of the origin and functional relevance of the 7 d domain of the biological time structure, with special reference to human beings. These biological rhythms are displayed at various levels of organization in diverse species – from the unicellular sea algae of Acetabularia and Goniaulax to plants, insects, fish, birds and mammals, including man – under natural as well as artificial, i.e. constant, environmental conditions. Nonetheless, very little is known about their derivation, functional advantage, adaptive value, synchronization and potential clinical relevance. About 7 d cosmic cycles are seemingly too weak, and the 6 d work/1 d rest week commanded from G-d through the Laws of Mosses to the Hebrews is too recent an event to be the origin in humans. Moreover, human and insect studies conducted under controlled constant conditions devoid of environmental, social and other time cues report the persistence of 7 d rhythms, but with a slightly different (free-running) period (τ), indicating their source is endogenous. Yet, a series of human and laboratory rodent studies reveal certain mainly non-cyclic exogenous events can trigger 7 d rhythm-like phenomena. However, it is unknown whether such triggers unmask, amplify and/or synchronize previous non-overtly expressed oscillations. Circadian (~24 h), circa-monthly (~30 d) and circannual (~1 y) rhythms are viewed as genetically based features of life forms that during evolution conferred significant functional advantage to individual organisms and survival value to species. No such advantages are apparent for endogenous 7 d rhythms, raising several questions: What is the significance of the 7 d activity/rest cycle, i.e. week, storied in the Book of Genesis and adopted by the Hebrews and thereafter the residents of nearby Mediterranean countries and ultimately the world? Why do humans require 1 d off per 7 d span? Do 7 d rhythms bestow functional advantage to organisms? Is the magic ascribed to the number 7 of relevance? We hypothesize the 7 d time structure of human beings is endogenous in origin – a hypothesis that is affirmed by a wide array of evidence – and synchronized by sociocultural factors linked to the Saturday (Hebrews) or Sunday (Christian) holy day of rest. We also hypothesize they are representative, at least in part, of the biological requirement for rest and repair 1 d each 7 d, just as the circadian time structure is representative, in part, of the biological need for rest and repair each 24 h.     

Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Intracranial recordings from human olfactory cortex reveal a characteristic spectrotemporal response to odors, including theta, beta and gamma oscillations, and show that high-frequency responses are critical for accurate perception of odors.     

Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms

Even though peripheral circadian oscillators in the cardiovascular system are known to exist, the daily rhythms of the cardiovascular system are mainly attributed to autonomic or hormonal inputs under the control of the central oscillator, the suprachiasmatic nucleus (SCN). In order to examine the role of peripheral oscillators in the cardiovascular system, we used a transgenic mouse where the Clock gene is specifically disrupted in cardiomyocytes. In this cardiomyocyte-specific CLOCK mutant (CCM) mouse model, the circadian input from the SCN remains intact. Both CCM and wild-type (WT) littermates displayed circadian rhythms in wheel-running behavior. However, the overall wheel-running activities were significantly lower in CCM mice compared to WT over the course of 5 weeks, indicating that CCM mice either have lower baseline physical activities or they have lower physical adaptation abilities because daily wheel running, like routine exercise, induces physical adaptation over a period of time. Upon further biochemical analysis, it was revealed that the diurnal oscillations of phosphorylation states of several kinases and protein expression of the L-type voltage-gated calcium channel (L-VGCC) α1D subunit found in WT hearts were abolished in CCM hearts, indicating that in mammalian hearts, the daily oscillations of the activities of these kinases and L-VGCCs were downstream elements of the cardiac core oscillators. However, the phosphorylation of p38 MAPK exhibited robust diurnal rhythms in both WT and CCM hearts, indicating that cardiac p38 could be under the influence of the central clock through neurohormonal signals or be part of the circadian input pathway in cardiomyocytes. Taken together, these results indicate that the cardiac core oscillators have an impact in regulating circadian rhythmicities and cardiac function.     

Continuity of Visual and Auditory Rhythms Influences Sensorimotor Coordination

People often coordinate their movement with visual and auditory environmental rhythms. Previous research showed better performances when coordinating with auditory compared to visual stimuli, and with bimodal compared to unimodal stimuli. However, these results have been demonstrated with discrete rhythms and it is possible that such effects depend on the continuity of the stimulus rhythms (i.e., whether they are discrete or continuous). The aim of the current study was to investigate the influence of the continuity of visual and auditory rhythms on sensorimotor coordination. We examined the dynamics of synchronized oscillations of a wrist pendulum with auditory and visual rhythms at different frequencies, which were either unimodal or bimodal and discrete or continuous. Specifically, the stimuli used were a light flash, a fading light, a short tone and a frequency-modulated tone. The results demonstrate that the continuity of the stimulus rhythms strongly influences visual and auditory motor coordination. Participants'' movement led continuous stimuli and followed discrete stimuli. Asymmetries between the half-cycles of the movement in term of duration and nonlinearity of the trajectory occurred with slower discrete rhythms. Furthermore, the results show that the differences of performance between visual and auditory modalities depend on the continuity of the stimulus rhythms as indicated by movements closer to the instructed coordination for the auditory modality when coordinating with discrete stimuli. The results also indicate that visual and auditory rhythms are integrated together in order to better coordinate irrespective of their continuity, as indicated by less variable coordination closer to the instructed pattern. Generally, the findings have important implications for understanding how we coordinate our movements with visual and auditory environmental rhythms in everyday life.     

Unravelling the Ecological Significance of Endogenous Rhythms in Intertidal Crabs

Organisms living along the shore are exposed to complex sets of environmental oscillations. In addition to solar (24.0 h) and lunar (24.8 h) cycles, local tides may reoccur on a 12.4 h schedule. Beyond daily routines, biweekly, monthly and annual rhythms may each have a significant impact on an animal's activity. For some time, it has been established firmly that intertidal crabs possess several internal biological clocks with distinctly different periods and properties. However, the versatility of these clocks has not been obvious. Crabs living in the littoral zone must adjust their internal chrono-meters to be synchronous with the specific temporal structure of the immediate habitat. Fine adjustments in their clocks will depend upon on a particular tide province and the location of their niche in the intertidal zone. Over a wide geographic range, the location of an intertidal habitat for one species may be in as many as four tidal provinces. Based on wave form and harmonic components, tide provinces are characterized as either a) semidiurnal, b) mixed, mainly semidiurnal, c) mixed mainly diurnal, or d) diurnal. Likewise, the primary frequency associated with an intertidal niche in each tide province may be augmented by diel (24 h) and semilunar (14 day) periods. In addition, supralittoral habitats may be influenced by monthly (28 day) and seasonal rhythms. Since some species live in several tidal provinces and different positions in the littoral zone, locomotor and larval release rhythms of intertidal crabs must naturally be adjusted to the timetable of the local habitat. Flexibility in ambulatory and egg hatching rhythms of crabs are discussed from this environmental perspective. The nature and location of the underlying circadian and tidal oscillators tracking these environmental rhythms are reviewed.     

Portrait of visual cortical circuits for generating neural oscillation dynamics

The mouse primary visual cortex (V1) has emerged as a classical system to study neural circuit mechanisms underlying visual function and plasticity. A variety of efferent-afferent neuronal connections exists within the V1 and between the V1 and higher visual cortical areas or thalamic nuclei, indicating that the V1 system is more than a mere receiver in information processing. Sensory representations in the V1 are dynamically correlated with neural activity oscillations that are distributed across different cortical layers in an input-dependent manner. Circuits consisting of excitatory pyramidal cells (PCs) and inhibitory interneurons (INs) are the basis for generating neural oscillations. In general, INs are clustered with their adjacent PCs to form specific microcircuits that gate or filter the neural information. The interaction between these two cell populations has to be coordinated within a local circuit in order to preserve neural coding schemes and maintain excitation–inhibition (E–I) balance. Phasic alternations of the E–I balance can dynamically regulate temporal rhythms of neural oscillation. Accumulating experimental evidence suggests that the two major sub-types of INs, parvalbumin-expressing (PV⁺) cells and somatostatin-expressing (SOM⁺) INs, are active in controlling slow and fast oscillations, respectively, in the mouse V1. The review summarizes recent experimental findings on elucidating cellular or circuitry mechanisms for the generation of neural oscillations with distinct rhythms in either developing or matured mouse V1, mainly focusing on visual relaying circuits and distinct local inhibitory circuits.     

Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations

Sleep-wake cycles break down with age, but the causes of this degeneration are not clear. Using a Drosophila model, we addressed the contribution of circadian mechanisms to this age-induced deterioration. We found that in old flies, free-running circadian rhythms (behavioral rhythms assayed in constant darkness) have a longer period and an unstable phase before they eventually degenerate. Surprisingly, rhythms are weaker in light-dark cycles and the circadian-regulated morning peak of activity is diminished under these conditions. On a molecular level, aging results in reduced amplitude of circadian clock gene expression in peripheral tissues. However, oscillations of the clock protein PERIOD (PER) are robust and synchronized among different clock neurons, even in very old, arrhythmic flies. To improve rhythms in old flies, we manipulated environmental conditions, which can have direct effects on behavior, and also tested a role for molecules that act downstream of the clock. Coupling temperature cycles with a light-dark schedule or reducing expression of protein kinase A (PKA) improved behavioral rhythms and consolidated sleep. Our data demonstrate that a robust molecular timekeeping mechanism persists in the central pacemaker of aged flies, and reducing PKA can strengthen behavioral rhythms.     

Robust Concentration and Frequency Control in Oscillatory Homeostats

Homeostatic and adaptive control mechanisms are essential for keeping organisms structurally and functionally stable. Integral feedback is a control theoretic concept which has long been known to keep a controlled variable robustly (i.e. perturbation-independent) at a given set-point by feeding the integrated error back into the process that generates . The classical concept of homeostasis as robust regulation within narrow limits is often considered as unsatisfactory and even incompatible with many biological systems which show sustained oscillations, such as circadian rhythms and oscillatory calcium signaling. Nevertheless, there are many similarities between the biological processes which participate in oscillatory mechanisms and classical homeostatic (non-oscillatory) mechanisms. We have investigated whether biological oscillators can show robust homeostatic and adaptive behaviors, and this paper is an attempt to extend the homeostatic concept to include oscillatory conditions. Based on our previously published kinetic conditions on how to generate biochemical models with robust homeostasis we found two properties, which appear to be of general interest concerning oscillatory and homeostatic controlled biological systems. The first one is the ability of these oscillators (“oscillatory homeostats”) to keep the average level of a controlled variable at a defined set-point by involving compensatory changes in frequency and/or amplitude. The second property is the ability to keep the period/frequency of the oscillator tuned within a certain well-defined range. In this paper we highlight mechanisms that lead to these two properties. The biological applications of these findings are discussed using three examples, the homeostatic aspects during oscillatory calcium and p53 signaling, and the involvement of circadian rhythms in homeostatic regulation.