Background

Neuroscience stands at the forefront of biology in the exploration of some of the most profound questions concerning living systems. The understanding of how nervous systems function and how they generate integrative behavior and cognition remain one of the most difficult challenges in science today. Currently, neuroscience is entering yet another era with the genomics and genetics revolution. The integration of neuroscience and genomics (“neurogenomics”), the use of molecular genetics to manipulate the mouse genome, and the use of novel molecular tools to define neural circuits are revolutionizing our ability to discover, define and decode the neural and genetic bases of behavior. The convergence of neuroscience and genetics has had a profound impact on the circadian field. This stems from two fundamental discoveries in the field: the localization of circadian pacemakers in the nervous systems of animals (e.g., the discovery of the suprachiasmatic nucleus (SCN) as the dominant pacemaker in mammals; and the isolation of circadian mutants and the subsequent cloning of circadian clock genes (e.g., the period locus in Drosophila and the Clock locus in mammals).

Circadian clocks have been described in organisms ranging from bacteria to humans and control numerous aspects of behavior, physiology, and biochemistry, including such things as sleep/wake cycles, locomotor activity, hormone synthesis, and visual sensitivity. These clocks are important for the normal homeostasis of the organism and disruption of these processes can contribute to human disorders. The last decade has witnessed a revolution in our understanding of the molecular mechanism of circadian clocks in animals, including the identification of at least seven different genes that are essential elements of the circadian clock mechanism (Clock, Bmal1, Per1, Per2, Cryptochrome1, Cryptochrome2 and Casein kinase 1 epsilon). With the initial discovery of these clock genes came the realization and documentation that the capacity for circadian expression is widespread throughout the body. Most peripheral organs and tissues can express circadian oscillations in isolation, yet still receive and may require input from the dominant circadian pacemaker in the suprachiasmatic nucleus (SCN) in vivo. The existence of both central and peripheral circadian oscillators raises a number of novel questions and hypotheses concerning the integration of the system to control the behavioral state of the organism.

Mission

Investigate how the multioscillatory circadian system of mammals can be regulated and entrained at the level of central and peripheral oscillators.

Strategy

  1. Test the hypothesis that central and peripheral oscillators both contribute to the normal physiological function and integration of the circadian system to regulate behavioral state. Tissue-specific, conditional regulation of circadian clock gene function in central vs. peripheral tissues will be used to test the role of these components in generating and entraining circadian behavior.
  2. Test the hypothesis that chemical and genetic tools can be used to manipulate the period and phase of circadian rhythms in mammals in a manner that is more efficacious than current methods which are based primarily on the use of environmental light manipulation, melatonin and nonphotic inputs. Specifically we will test the hypothesis that small molecules can reset circadian rhythms in mammals more efficiently than light cycles because these molecules should have direct access to both central and peripheral oscillators, whereas, light cycles can only access the circadian system via the retina and suprachiasmatic nucleus.
  3. Test the mechanism of action of chemical and genetic tools discovered in Strategy 2 by assessing their molecular targets and validating these agents at the cellular and organismal level. Human genetic variants in circadian clock gene targets will also be used to evaluate the efficacy and specificity of these tools in mouse models of these human disorders.