Circadian clock proteins control adaptation to novel environment and memory formation

Anna A.Kondratova,Roman V Kondratov,Marina P Antoch,Yuliya V.Dubrovsky

doi:10.18632/aging.100142

Abstract

Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, 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 behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-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 with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning.

Highlights

The ability to explore the outside world and compare old and new information is critical for animal’s survival
Our results demonstrate that habituation to novelty is differentially altered in mice with a deficiency/mutation of the core circadian genes Bmal1, Clock, or Cry1 and Cry2 and correlates with the transcription activity status of the BMAL1:CLOCK: [CRY1,2] complex
Severe deficiency in the intersession habituation demonstrated by Bmal1-/- and Clock/Clock mice both in locomotion and rearing suggests that Bmal1-/- and Clock/Clock mice lack memory of the previous day experience and allows speculating that transcription activity of the BMAL1:CLOCK complex is necessary for the LTM formation, which requires de novo synthesis of both RNA and protein [31]

Summary

INTRODUCTION

The ability to explore the outside world and compare old and new information is critical for animal’s survival. Habituation, one of the simplest forms of non-associative learning, is the mechanism providing an animal with the means to dampen the perception of repetitive neutral stimuli and be ready to effectively detect a novel stimulus with a yet unknown significance, and is vitally important for the interaction of an organism with its environment [1,2,3] Both response to novelty and habituation change with age, but molecular mechanisms underlying these changes remain mostly unknown. We hypothesize that the circadian clock is involved in the regulation of the adaptation to the new environment, and investigate this hypothesis using a set of circadian mutants - mice with targeted disruptions of circadian genes Bmal or Cry and Cry, or with the mutation of the Clock [12,13,14] gene These genes encode proteins representing the core components of the circadian clock. CRY1 and CRY2 suppress activity of the BMAL1:CLOCK complex, including their own expression, generating a negative feedback loop; expression of several other genes important for the functional clock (i.e. Per and 3) is under the transcription control of the BMAL1:CLOCK complex [15]

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES