Mathematical insights into the role of dopamine signaling in circadian entrainment.

The circadian clock in the mammalian brain comprises interlocked molecular feedback loops that have downstream effects on important physiological functions such as the sleep-wake cycle and hormone regulation. Experiments have shown that the circadian clock also modulates the synthesis and breakdown of the neurotransmitter dopamine. Imbalances in dopamine are linked to a host of neurological conditions including Parkinson's disease, attention-deficit/hyperactivity disorder, and mood disorders, and these conditions are often accompanied by circadian disruptions. We have previously created a mathematical model using nonlinear ordinary differential equations to describe the influences of the circadian clock on dopamine at the molecular level. Recent experiments suggest that dopamine reciprocally influences the circadian clock. Dopamine receptor D1 (DRD1) signaling has been shown to aid in the entrainment of the clock to the 24-hour light-dark cycle, but the underlying mechanisms are not well understood. In this paper, we use our mathematical model to support the experimental hypothesis that DRD1 signaling promotes circadian entrainment by modulating the clock's response to light. We model the effects of a phase advance or delay, as well as the therapeutic potential of a REV-ERB agonist. In addition to phase shifts, we study the influences of photoperiod, or day length, in the mathematical model, connect our findings with the experimental and clinical literature, and determine the parameter that affects the critical photoperiod that signals seasonal changes to physiology.

Duke Scholars

Author H. Frederik Nijhout Biology

Author Michael C. Reed Mathematics