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Neurons and networks in daily rhythms

Key Points

  • The nervous system is never silent, and neurons often show daily rhythms in their gene and electrical activities.

  • These rhythms arise from near 24-hour feedback loops that involve identified genes and their protein products.

  • Cellular events that modulate the amplitude and phase of circadian rhythms (including changes in membrane potential and kinase activity) ultimately synchronize circadian cells to each other and to daily environmental cycles.

  • Neurons in several species have been identified as circadian pacemakers for a variety of behaviours, including locomotion, olfaction and learning.

  • All cell types in the body might be capable of intrinsic circadian oscillations.

  • Synaptic strengths change as a function of time of day.

  • The connections between circadian cells and tissues include synaptic and hormonal signals, only some of which have been identified.

  • Daily rhythms in behaviour are normal, and they segregate neural events into sequences that allow the organism to prepare for predictable changes in the environment, such as the availability of sensory cues (for example, light or odour intensity), partners, predators and prey.

Abstract

Biological pacemakers dictate our daily schedules in physiology and behaviour. The molecules, cells and networks that underlie these circadian rhythms can now be monitored using long-term cellular imaging and electrophysiological tools, and initial studies have already suggested a theme — circadian clocks may be crucial for widespread changes in brain activity and plasticity. These daily changes can modify the amount or activity of available genes, transcripts, proteins, ions and other biologically active molecules, ultimately determining cellular properties such as excitability and connectivity. Recently discovered circadian molecules and cells provide preliminary insights into a network that adapts to predictable daily and seasonal changes while remaining robust in the face of other perturbations.

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Figure 1: A simple, standard model of the molecular basis for circadian rhythm generation.
Figure 2: Circadian pacemakers of snails, flies and mice.
Figure 3: Circadian plasticity.
Figure 4: Analysis of pinch-points in the circadian gene network in mammals.
Figure 5: Why oscillate?

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Acknowledgements

I am deeply grateful to the members of the Washington University Clocksclub (the laboratories of R. Van Gelder, P. Taghert, P. Shaw, L. Muglia and P. Gray) and to M. Hastings, D.-J. Dijk and B. Schwartz for their guidance on this Review. This work was supported by US National Institutes of Health (MH63104 and GM78993) and National Science Foundation (425445) grants.

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DATABASES

OMIM

familial advanced sleep phase syndrome

major depressive disorder

FURTHER INFORMATION

Erik D. Herzog's homepage

Database of Circadian Gene Expression

Glossary

Clock genes

A class of genes, the primary function of which is to participate in a transcription–translation negative-feedback mechanism that generates a near 24-hour rhythm in physiology.

Cell-autonomous

Intrinsic to a single cell. Circadian rhythm generation and output is a property of circadian pacemaking cells.

Advanced sleep phase syndrome

An autosomal-dominant sleep disorder that is characterized by early sleep onset and offset.

Metazoan

An animal belonging to the subkingdom Metazoa, which comprises multicellular animals that have cells that are differentiated into tissues and organs. The Metazon subgroup includes all animals except protozoans and sponges.

Free-running rhythm

An oscillation that persists in the absence of any external input, for example, circadian rhythms in unchanging conditions. When environmental (entraining) cues are eliminated, the intrinsic period of the system is revealed.

Eclosion

The emergence of an adult insect from its pupal case. In many insects, the timing of this emergence is regulated by the circadian clock.

Malpighian tubules

The insect analogue of the kidney. In flies, these excretory tubules express circadian ryhthms in gene expression in vitro and in vivo, even when transplanted into behaviourally arrhythmic flies.

Real-time reporter

A molecular probe that provides information about the level or activity of intracellular events with high temporal resolution compared to the kinetics of the process that is being studied.

Photoperiodism

The biological response to a change in day length. Examples of photoperiodic responses include flowering on long days and storing fat on short days.

Sensitivity analysis

An engineering approach to determine which processes are susceptible to perturbation. The basic strategy is to vary parameters (for example, the maximal transcription rate of the period gene, or the binding rate of the period and cryptochrome proteins) in a model and measure the effect on a specific process (for example, the amplitude or period of circadian oscillations in period proteins). Parameters that cause larger changes in the output when varied over a smaller range are deemed more sensitive.

Cis regulatory region

A segment of DNA physically proximal to a gene that controls the level and timing of that gene's expression. Promoter elements like E-boxes and RREs are found in the cis regulatory regions.

E box

An evolutionarily conserved nucleotide sequence (either CACGTG or CACGTT) in the promoter (cis regulatory) regions of some genes. Through binding of the transcription factors clock and BMAL1, E boxes regulate these genes' circadian expression.

D box

Also known as the DBP/E4BP4 binding element. An evolutionarily conserved nucleotide sequence (TTA[T/C]GTAA, where [T/C] indicates thymidine or cytosine) in the promoter (cis regulatory) regions of some genes. Through binding of specific transcription factors, D boxes regulate these genes' circadian expression.

RRE

Also known as the RevErbA/ROR binding element. An evolutionarily conserved nucleotide sequence ([A/T]A[A/T]NT[A/G]GGTCA, where [A/T] indicates adenosine or thymidine and N indicates any nucleotide) in the promoter (cis regulatory) regions of some genes. Through binding of the transcription factors RevErb and ROR, RREs regulate these genes circadian expression.

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Herzog, E. Neurons and networks in daily rhythms. Nat Rev Neurosci 8, 790–802 (2007). https://doi.org/10.1038/nrn2215

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