Christopher S. Colwell
The focus of our research is circadian rhythms and sleep. Most organisms, including humans, exhibit daily rhythms in their behavior and physiology. In most cases, these rhythms are generated by endogenous processes referred to as circadian oscillators. These oscillators provide temporal structure to an organismís physiological processes. Nearly all functions of the body show significant daily variations including arousal, cognition, learning, memory, motor performance and perception. This temporal variation obviously plays an important role in the bodyís homeostatic mechanisms and has a major impact on the function of the nervous system. Mammals have evolved a set of anatomically discrete cell populations that function as a physiological system to provide temporal organization on a circadian time scale. These structures are commonly referred to as the circadian system and can be localized to a pair of structures in the hypothalamus known as the suprachiasmatic nucleus or SCN. Importantly, when SCN cells are removed from the organism and maintained in a brain slice preparation, they continue to generate 24-hour rhythms in electrical activity, secretion, and gene expression. Previous studies suggest that the basic mechanism responsible for the generation of these rhythms is intrinsic to individual cells in the SCN. In order to function adaptively, these cells must be synchronized to the exact 24 hr cycle of the physical world. The daily cycle of light and dark is the dominant cue used by organisms, including humans, to synchronize their biological clocks to the environment. Therefore, in the simplest case, a circadian system can be modeled as having three components: 1) input pathways by which the environment and other components of the nervous system provide information to the SCN, 2) an oscillator or clock within the SCN responsible for the generation of the daily rhythm, and 3) output pathways by which the SCN provides temporal information to a wide range of physiological and behavioral control centers. The long-term goal of our basic research program is to understand each of these three components at different levels of organization from systems to molecular.
Over the last few years, our research program has been making a major shift towards more translational research. This shift is driven by the compelling clinical data indicating that many patients with diseases of the nervous system exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day. This dysfunction in timing is not a causal to their disorder yet these symptoms have a major impact on the quality of life of the patient population and on the family members who care for the patients. Our strategy is to explore mouse models of the human disease and behaviorally determine the impact of the mutations on circadian rest/ activity cycle. No single mouse model can be expected to recapitulate all aspects of the human disease. We would like to know to what extent circadian dysfunction is a common feature of the mouse models. If we find behavioral deficits that mimic the condition of human patients, we will then explore these deficits using physiological and molecular tools with a focus on the site of the biological clock in the hypothalamus, the SCN. Finally, we will examine the impact of interventions designed to improve the sleep and circadian function of the mouse models. It is our goal to develop novel interventions that will improve the motor and cognitive performance of patients.
Department of Psychiatry and Biobehavioral Sciences
Intellectual and Developmental Disabilities Research Center
University of California, Los Angeles
760 Westwood Plaza
Los Angeles, CA 90024
Phone: (310) 206-3973
FAX: (310) 206-5060