Circadian rhythms and memory: not so simple as cogs and gears

Abstract

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

Figure 1

Is memory training a zeitgeber for hippocampal neurons? In view of the molecular similarities between the processes of light-induced phase shifting in suprachiasmatic nucleus neurons and hippocampal memory consolidation, memory training could induce a distinct phase-response curve in memory-specific neuronal ensembles. The initial spike drawn in the phase-response curve after a training event reflects the early increase in mitogen-activated protein kinase activity and gene expression that occurs in many hippocampal neurons after a training event. Depending on when training occurs relative to existing circadian oscillations, the phase response might be advanced, delayed or unchanged. If unchanged, there could be increased phase coupling between neurons or an increase in the amplitude of oscillations in neurons that are already keeping time. One of these outcomes might be preferable for the hippocampal–cortical communication that occurs during slow-wave sleep. Phase-adjusted or amplitude-adjusted neurons could be marked and selected for the subsequent transfer and storage of information in the cortex.

Figure 2

Memory training: one hippocampal input among many. Memory consolidation occurs within the context of fluctuating states of synaptic plasticity in the hippocampus. The regulation of hippocampal neurons by the sleep-wake cycle, circadian cues and, possibly, the expression of circadian clock genes dynamically alters the state of plasticity on which a training response can be generated. A few of the molecules and proteins that could link the circadian clock and sleep to hippocampal plasticity are listed, as well as how they might affect memory consolidation mechanistically. The integration of these inputs in the hippocampus might determine the functional output, memory, at the level of formation and maintenance. Bmal1, brain and muscle aryl hydrocarbon receptor nuclear translocator (Arnt)-like protein-1; Cry, cryptochrome; GABA, γ-aminobutyric acid; Npas2, neuronal period–aryl hydrocarbon receptor nuclear translocator–single-minded domain protein 2; Per, period.

Kristin L. Eckel-Mahan

Daniel R. Storm