OHSU

Butler Clock Physiology Lab

Disruptions of internal body clocks, such as encountered by shift workers, are a risk factor for a host of maladies, including cardiovascular disease and metabolic disorders.  Our goals in this laboratory are to understand how endogenous clocks in the body are synchronized, and how uncoupling clocks from the environment or from each other can compromise health. Our methods of inquiry include external and internal clock disruption models in rodents, controlled investigations of human physiology, and prospective and cross-sectional analyses of long term human sleep study cohorts. At the Oregon Institute of Occupational Health Sciences, we have a unique opportunity to move basic studies directly to the clinical research setting.

Uncoupling clocks with light and food

The focal point of our laboratory is rodent studies of clock disruption, and the physiological, metabolic, and behavioral outcomes that ensue.  We house a variety of reporter mice strains in cages with custom feeders that can impose a range of food schedules, either in or out of phase with ambient light cycles.  Peripheral clock gene rhythms are documented in vivo via bioluminescence and can be tracked longitudinally with other endpoints such as locomotor activity and glucose handling. Other outcomes include the relationship of clock gene desynchrony with cardiovascular function and anatomy, liver function, and the integration and readout of endogenous rhythms within the hypothalamus. The spirit of these rodent studies is to characterize novel mechanisms, to generate predictions that can apply to human diseases where the clock has been implicated.

Human Circadian Biology

A hurdle in all animal studies of circadian clocks is that it is hard to disentangle the covarying effects of the endogenous circadian clock from the effects of the sleep-wake or fasting-feeding cycles. In contrast, human volunteers provide a unique way to separate these conflicting cycles, and indeed, we find that overt rhythms are sometimes more attributable to the clock, sometimes more attributable to sleep or eating. In a forced desynchrony protocol, participants live for many days in a laboratory suite without any time cues. By varying the length of the time awake and asleep or by manipulating the time of meals, these can be separated from the underlying and free-running circadian clock. We have used forced desynchrony methods to examine how the internal circadian time affects the cardiovascular response to stressors such as orthostatic tolerance and exercise. We have also employed a similar protocol to determine the extent to which circadian rhythms underlie the durations and incidence of apneas (periods where breathing ceases) during sleep. The utility of a forced desynchrony lies in deciphering how the circadian, feeding, and sleep processes sum to control overt physiology. These studies are guided by and provide motivation for the parallel studies of animals

Prospective Sleep Studies of Sleep Apnea

What are the real world implications of our work? Sleep apnea is prevalent in up to 20% of the population, and is a risk factor for hypertension, heart failure, obesity, and diabetes. Nevertheless, its diagnosis remains limited to an assessment of the average number of apneas and hypopneas per hour of sleep, and convenient but coarse index. In collaboration with Dr. Susan Redline, we are using the newly available public sleep data repositories to determine whether temporal patterns of apnea incidence and their duration during sleep may better predict comorbidities of sleep apnea.