Ruby Kim
The superchiasmatic nucleus (SCN) serves as the primary circadian (24hr) clock in mammals, and is known to control important physiological functions such as the sleep-wake cycle, hormonal rhythms, and neurotransmitter regulation. Experimental results suggest that some of these functions reciprocally influence circadian rhythms, creating a complex and highly homeostatic network. Among the clock's downstream products, orphan nuclear receptors REV-ERB and ROR are particularly interesting because they coordinately modulate the core clock circuitry. Recent experimental evidence shows that REV-ERB and ROR are not only crucial for lipid metabolism, but are also involved in dopamine (DA) synthesis and degradation, which could have meaningful clinical implications for conditions such as Parkinson's disease and mood disorders.
We create a mathematical model that includes the circadian clock, REV-ERB and ROR and their feedback to the clock, and the influences of REV-ERB, ROR, and BMAL1-CLOCK on the dopaminergic system. We compare our model predictions to experimental data on clock components in different light-dark conditions and in the presence of genetic perturbations. Our model results are consistent with experimental results on REV-ERB and ROR and allow us to predict circadian oscillations in extracellular dopamine and homovanillic acid that correspond well with observations.
The predictions of the mathematical model are consistent with a wide variety of experimental observations. Our calculations show that the mechanisms proposed by experimentalists by which REV-ERB, ROR, and BMAL1-CLOCK influence the DA system are sufficient to explain the circadian oscillations observed in dopaminergic variables. Our mathematical model can be used for further investigations of the effects of the mammalian circadian clock on the dopaminergic system. RR{The model can be used to predict how perturbations in the circadian clock disrupt the dopamine system and could potentially be used to find drug targets that ameliorate these disruptions.
