Chapter 18 - Feedback actions of locomotor activity to the circadian clock
Introduction
The rotation of the Earth about its axis imposes upon the vast majority of living organisms predictable daily cycles with a period of ∼ 24 h. In order to perform optimally in an appropriate temporal niche, organisms have developed corresponding cyclic rhythms in their own behavioral and physiological functions. A feature of these daily, or circadian, rhythms (derived from the Latin circa, meaning about, and dies, a day) is that they are generated by endogenous circadian clocks expressed within the cells and tissues of an organism and continue to oscillate with a period of close to 24 h even when the organism is isolated from all external timing influences. Endogenous circadian oscillators are thought to confer a selective advantage on organisms through predictive homeostasis; organisms are able to anticipate predictable environmental events, such as dusk and dawn or times of high predator/prey activity, before they occur and can therefore prepare appropriately (Piggins and Guilding, 2011). Indeed, the lack of a circadian clock can influence survival in a natural environment (DeCoursey et al., 2000), and possession of a clock that runs with an inappropriate cycle length is disadvantageous in laboratory-based competition studies (Woelfle et al., 2004).
The mammalian circadian system consists of input pathways (Fig. 1), a central “master” pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus, numerous extra-SCN oscillators distributed throughout the brain and body, and output pathways to effect changes in the temporal organization of physiology and behavior (Golombek and Rosenstein, 2010, Kalsbeek et al., 2006). Anatomically, the SCN can be loosely divided into two subregions, one characterized by expression of the neuropeptide vasoactive intestinal polypeptide (VIP) that receives heavy external input from the retina and other regions of the brain, and the remainder of the SCN that receives somewhat lighter extra-SCN innervation (Abrahamson and Moore, 2001, Morin, 2007). The SCN generates rhythms of high- and low-neuronal discharge (Brown and Piggins, 2007) driven by an interlocking network of core clock genes and other rhythmic processes (Glossop, 2011, Hastings et al., 2008, Ko and Takahashi, 2006), though recent evidence indicates that the electrical output of the SCN is more complex than this simple model suggests (Belle et al., 2009). Under normal environmental and physiological conditions, the SCN dominates the circadian system of mammals, coordinating the phase of rhythms in the various tissue-specific extra-SCN oscillators (see Dibner et al., 2010, Guilding and Piggins, 2007).
To benefit an organism, endogenous circadian rhythms must be maintained in phase with environmental time cues. In addition to specific chemical agents such as melatonin (van Geijlswijk et al., 2010), certain stimuli including light and a variety of light-independent, or nonphotic, cues are capable of phase-dependently phase resetting the circadian system. Repeated exposure to these signals at appropriate times can synchronize, or entrain, the circadian system to the environment (Golombek and Rosenstein, 2010). The purpose of this review is to collate and summarize the phase resetting and entraining actions of locomotor activity feedback to the mammalian circadian system.
Section snippets
Photic entrainment
The most ubiquitous entraining stimulus, or zeitgeber, encountered in daily life for the majority of organisms is that of the light–dark (LD) cycle of the solar day; therefore, to fully appreciate nonphotic influences on the circadian system, we must first briefly consider photic entrainment. As the endogenous SCN-driven period of circadian rhythms for most mammals differs slightly from 24 h, rhythms must be periodically shifted back toward external environmental time in order to maintain an
Nonphotic entrainment
The concept that circadian rhythms could be influenced by mechanisms other than light came to prominence in the mid-1960s through a series of experiments demonstrating that the rhythms of birds could be entrained to the daily playback of birdsong (Gwinner, 1966, Menaker and Eskin, 1966). These experiments, along with early reports of social entrainment in humans (Aschoff, 1979, Wever, 1979) elegantly revealed that circadian rhythms could be altered using so-called nonphotic mechanisms; that is,
Locomotor activity as a nonphotic stimulus
A number of techniques can be used to induce locomotor activity in laboratory rodents including confinement to a novel-running wheel, injections of some benzodiazepines, and forced treadmill running (e.g., Mistlberger, 1991a, Mistlberger, 1991b, Mrosovsky and Salmon, 1987, Turek and Losee-Olson, 1986). Each of these, along with scheduled voluntary wheel access (Edgar and Dement, 1991), has been used extensively to investigate the effects of overt locomotor activity on circadian function.
The
Interactions between nonphotic and photic entraining stimuli
Previously in this review, we have considered the well-characterized effects of both light and nonphotic influences on the phase of behavioral circadian rhythms. While in the laboratory we aim to control variables in order to determine responses to specific stimuli, in nature, it would be more common for different zeitgeber modalities to be encountered in combination. Responses of the mammalian circadian system to photic and nonphotic stimuli are both mediated by effects on the central SCN
Entrainment to exercise: Longer-term effects of locomotor activity
We have, up to now, considered the short-term effects of acute “pulses” of locomotor activity on free-running circadian rhythms in constant conditions and the ability of such pulses to modify the reentrainment of behavior following LD shifts. In addition to these acute effects, ad libitum access to a running wheel, and hence daily, though unscheduled, vigorous locomotor exercise also feeds back to regulate central circadian function. The presence of a home-cage running wheel shortens tau in
The roles of arousal and physiological correlates of locomotor activity in entrainment
The role of exercise/locomotor activity in entrainment is intimately linked with the arousal state of an animal (Mrosovsky, 1996), and to date, even 25 years after the first reports of locomotor activity feeding back to the central oscillator, the precise nature of this signal has yet to be resolved. It is clear that locomotor activity feedback can alter circadian phase, both acutely and as stable entrainment, however, it is unknown which aspect or combination of aspects of locomotor activity
Molecular basis of phase shifts
At the molecular level, circadian rhythms are generated within cell autonomous pacemakers through the rhythmic expression of a network of core clock genes and their proteins, including, among others, the period (per) genes, per1 and per2, the cryptochrome 1 and 2 genes and bmal1. Our current understanding of the components and workings of this core molecular oscillator has been extensively reviewed elsewhere (Glossop, 2011, Ko and Takahashi, 2006), so this discussion shall be limited to the
Nonphotic entrainment in diurnal species
Increasing numbers of studies demonstrating temporal niche switching are blurring the distinction between species traditionally considered in the laboratory to be “nocturnal” or “diurnal” (reviewed in Kronfeld-Schor and Dayan, 2008). Nevertheless, the vast majority of nonphotic entrainment research to date, and indeed circadian research in general, has been carried out on rodents that exhibit nocturnal activity patterns under normal laboratory conditions. Studies of species that exhibit diurnal
Aging
Age-related changes in circadian function in animals are well documented. Phase angle of entrainment to LD becomes more positive, variability in onsets increases, and behavioral rhythms fragment and lose amplitude (Weinert, 2000). SCN function also appears to weaken, with lower amplitude oscillations in electrical function (Biello, 2009, Nakamura et al., 2011, Watanabe et al., 1995) and reduced responsiveness to photic stimuli (Kolker et al., 2003). Older animals perform fewer spontaneous
Future directions
A number of key issues surrounding the feedback influences of locomotor activity on the circadian system have yet to be addressed. Species generalization continues to be an issue; the bulk of early work was carried out on hamsters, with rats and mice very much underrepresented. This has been redressed to some extent but, as with most research in the postgenomic age where mice have become the species of choice, there is now a risk of overspecializing and becoming limited to this alternative
Zeitgeber versus zeitnehmer?
Traditionally, chronobiologists have used the term zeitgeber, literally meaning “time giver,” to describe any external stimulus that is rhythmically encountered and acts as an entraining signal to the circadian system. This term, and its implication of a one-way transfer of information from the environment to the circadian system, appropriately describes independent external stimuli such as the LD cycle. However, the consideration of an internally controlled function, such as locomotor
Summary and conclusions
Once thought of as simply an output, locomotor activity has for some time been known to also provide a feedback signal to the circadian system. Discrete pulses of locomotor activity can shift circadian phase or modify reentrainment to a shifted LD cycle, while scheduled locomotor activity can entrain circadian behavior and even induce lasting improvements in pacemaker function in circadian mutants. The precise nature of the feedback signal is unknown but is likely to be complex, involving a
Acknowledgments
The authors would like to thank Prof. Ralph Mistlberger for critical comments on an earlier draft of this review and acknowledge the BBRSC and Wellcome Trust for financial support of their work.
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