Circadian rhythmogenesis from neuromodulator- and molecular clock-mediated network mixed feedback*

Abstract

The suprachiasmatic nucleus (SCN) is a subset of neurons in charge of timekeeping circadian phenomena. As a network, it is capable of maintaining periodic activity with stable phase-locking patterns in spite of heterogeneous nodes. The mechanisms underlying SCN rhythmogenesis are still largely debated. We propose a novel biophysical SCN network model in which circadian rhythmicity emerges from the interaction of neuromodulator-mediated network positive feedback and molecular clock-mediated cellular negative feedback. Because neuromodulator action is much faster than molecular clock dynamics, our model reveals that the same “mixed” (i.e., fast positive, slow negative) feedback governing neuronal excitability also rules circadian oscillations but on several orders of magnitude slower timescales. It also reveals that, when dynamics are sufficiently slow, neuromodulators can create, instead of solely modulate, feedback loops. A mathematical abstraction of the derived SCN network makes novel predictions about the action of various SCN neuromodulators.