Butler Clock Physiology Lab
Research InterestsDisruptions of our internal body clocks and sleep, as often encountered by shift workers, increase the risk for disease. Our goals in this laboratory are to understand how endogenous clocks in the body are synchronized, and how these regulate physiology and behavior. Our methods of inquiry include neuroendocrinology and behavior studies in mouse models and prospective and cross-sectional cohort studies to inform our approaches.
Androgen receptors and sex differences in the circadian clockThe premise of this research is that androgens compensate for organizational sex differences in the brain's clock by altering the sensitivity of the clock to photic inputs. To understand the mechanisms, we analyze the role of androgen receptor containing neurons using electrophysiology, slice imaging and network mapping, and functional studies of behavior using DREADDs. The goal is to determine the cellular and network properties of entrainment specifically and of sex differences in neurobiology more generally. Collaborators: Chuck Allen and Rae Silver.
Figure 1: Reversibility
of free-running period. When a mouse is
gonadectomized, its free-running period lengthens. We have discovered that this
is due to a hormonal effect on light sensitivity. After
gonadectomy (star), the period is long in constant dim red light
(red shading), but short in constant darkness
Figure 2: Androgen receptors (AR, green) are strongly expressed in the core of
the SCN –the primary area receiving input from the retina. The
shell of the SCN is marked by arginine vasopressin (AVP, red). After
gonadectomy (GDX), AR expression drops.
Reproductive Consequences of Shift Work
A focal point of our laboratory is rodent studies of clock disruption, and the physiological, metabolic, and behavioral outcomes that ensue. We are currently working to understand how uncoupling of light-dark cycle with feeding-fasting cycles (essentially a model of night-eating) compromises fertility in mice. The goal is to determine the clock mechanisms in the brain and peripheral tissues that may explain the epidemiological patterns of poor reproductive outcomes in shift workers. To better understand context, we also employ human cohort studies to understand the public health impact of shift work. Collaborator: Jin Ho Park.
Figure 3: The Period2 clock gene cycles rhythmically in the uterus and ovary in vitro.
Gender differences in the association of sleep apnea, heart disease, and mortality
Sleep apnea is a risk factor for hypertension, heart failure, obesity, and diabetes. Treatment decisions are made by the the average number of apneas and hypopneas per hour of sleep, but this measure does not predict future risk in women. In this NIH-funded study, we we employ sleep data repositories to identify new metrics based on the temporal patterns of apnea that better predict apnea-related morbidity and mortality in both men and women. Collaborators: Steven A Shea and Susan Redline.
Figure 4: Respiratory event duration variability. This figure shows the strong inter-individual variability in the duration of obstructive events. All ten subjects had an apnea hypopnea index of 40, but mean duration ranged from 19 to 41 sec. We have found that short events are significant predictors of mortality, independent of AHI.