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Circadian rhythms and memory formation

Key Points

  • The regulation of memory formation by circadian rhythms and/or time-of-day effects is phylogenetically conserved in many species — including invertebrates and vertebrates — and correlates with cycling levels of melatonin.

  • These features may be independent of changes in behavioural state (that is, wakefulness and sleep).

  • The time-of-day-dependent regulation of neurophysiological parameters, such as spontaneous firing rate and resting membrane potential of neurons, are also phylogenetically conserved between invertebrate and vertebrate models.

  • Circadian and time-of-day-dependent regulation of synaptic plasticity occurs in various mammalian models and can be considered a natural form of metaplasticity.

  • Across phylogeny, similar molecular machinery underlies the processes of generating circadian rhythms and memory formation. These involve the expression of clock genes and the cyclic AMP–mitogen-activated protein kinase (MAPK)–cAMP-responsive element-binding protein (CREB) cascade.

  • The maintenance of long-term memory seems to require oscillation of the cAMP–MAPK–CREB pathway. From these data, a model emerges suggesting that this maintenance of memory requires essentially autonomous molecular oscillators within memory-forming cells.

Abstract

There has been considerable progress in elucidating the molecular mechanisms that contribute to memory formation and the generation of circadian rhythms. However, it is not well understood how these two processes interact to generate long-term memory. Recent studies in both vertebrate and invertebrate models have shown time-of-day effects on neurophysiology and memory formation, and have revealed a possible role for cycling molecules in memory persistence. Together, these studies suggest that common mechanisms underlie circadian rhythmicity and long-term memory formation.

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Figure 1: Phylogenetic conservation of the core molecular clock.
Figure 2: Anatomical circadian pathways in flies and mice.
Figure 3: Time-of-day-dependent neurophysiology in pacemaker cells.
Figure 4: Time-of-day effects on synaptic plasticity.
Figure 5: Melatonin and circadian rhythms of memory.
Figure 6: Models for the circadian regulation of memory.

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Acknowledgements

The authors thank C. F. Landry for his useful comments on this manuscript.

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Glossary

Zeitgeber

A German word that means 'time-giver'. It refers to an exogenous cue, such as the light–dark cycle, that entrains a circadian rhythm.

Circadian rhythm

The regular cycling of biological processes in an organism over a 24-hour period that occurs regardless of the zeitgeber.

Time-of-day effect

The effect of the specific point in time during the day–night cycle on the biological processes of an organism. The effect can be dependent or independent of a zeitgeber.

Long-term potentiation

A persistent increase in synaptic strength following high-frequency stimulation of a synapse.

Crepuscular

Describes an organism that is active during twilight or during day-to-night or night-to-day transitions.

Eclosion rhythm

The timing of the emergence of the adult fly from its pupal case, which usually occurs at dawn.

Clock gene

A gene that regulates aspects of circadian rhythms.

Suprachiasmatic nucleus

A hypothalamic bilateral structure that is the central pacemaker of circadian rhythms in mammals.

Melatonin

A catecholamine hormone derived from serotonin.

Hofbauer–Buchner eyelets

Photoreceptor cells that are located between the retina and the lamina of the fly eye.

Metaplasticity

Alterations in the ability of the synapse to change in strength.

Inhibitory avoidance conditioning

A form of learning in which an animal learns to avoid a stimulus (for example, a darkened compartment) that delivers a shock.

Zeitgeber time

(ZT). Standardized notation for the time during an entrained circadian cycle. ZT0 is the start of the light phase and ZT12 is the beginning of the dark phase, during a 24-hour light–dark cycle.

Epigenetic mechanism

A process that alters the state of gene expression through changes in chromatin structure (that is, DNA or histone modifications).

Circadian time

(CT). Standardized notation for an organisms relative (subjective) time. CT0 is the start of subjective daytime and CT12 is the start of subjective night-time, under constant dark conditions, over 24 hours.

Fear conditioning

A form of learning in which fear is associated with a neutral stimulus, by pairing the neutral stimulus with an aversive stimulus. In contrast to inhibitory avoidance conditioning, the animal cannot choose to avoid the conditioned stimulus upon testing.

Time stamp

The time of day that produces optimal performance in a memory task and is associated with the memory.

Engram

A hypothetical representation of the physiological storage of memory.

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Gerstner, J., Yin, J. Circadian rhythms and memory formation. Nat Rev Neurosci 11, 577–588 (2010). https://doi.org/10.1038/nrn2881

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