Circadian clock proteins control adaptation to novel environment and memory formation

Abstract

Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated agingphenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-basedactivities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behaviorand habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factorBMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- andlong-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice withmutation in the Clock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity andimpaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatialmemory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in thebrain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the properexploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities throughoptimization of behavioral learning. © Kondratova et al.