Limits of entrainment of circadian neuronal networks.

Circadian rhythmicity lies at the center of various important physiological and behavioral processes in mammals, such as sleep, metabolism, homeostasis, mood changes, and more. Misalignment of intrinsic neuronal oscillations with the external day-night cycle can disrupt such processes and lead to numerous disorders. In this work, we computationally determine the limits of circadian synchronization to external light signals of different frequency, duty cycle, and simulated amplitude. Instead of modeling circadian dynamics with generic oscillator models (e.g., Kuramoto-type), we use a detailed computational neuroscience model, which integrates biomolecular dynamics, neuronal electrophysiology, and network effects. This allows us to investigate the effect of small drug molecules, such as Longdaysin, and connect our results with experimental findings. To combat the high dimensionality of such a detailed model, we employ a matrix-free approach, while our entire algorithmic pipeline enables numerical continuation and construction of bifurcation diagrams using only direct simulation. We, thus, computationally explore the effect of heterogeneity in the circadian neuronal network, as well as the effect of the corrective therapeutic intervention of Longdaysin. Last, we employ unsupervised learning to construct a data-driven embedding space for representing neuronal heterogeneity.