Collaborative research: Multiscale modeling of the physiological interactions between sleep and circadian systems

Colorado School Of Mines, Golden CO

Investigators

Abstract

Understanding the interactions between sleep/wake behavior and the circadian (~24 hour) rhythm, coordinated in the brain by the suprachiasmatic nucleus (SCN), is fundamentally important for coping with challenges associated with shift work, jet lag, and, more generally, life in our 24-hour society. When these systems are not optimally aligned, there are negative implications for physical and mental health, job performance, and key tasks such as driving. Investigating these interactions is difficult since they take place on a range of spatial and temporal scales that are not easily addressed simultaneously with current experimental techniques. Temporal scales vary from the millisecond timing of neuron firing to the 24 hour period of the circadian rhythm to the days and weeks over which misalignment of sleep and circadian rhythms occurs. Spatial scales range from the intracellular protein transcription and translation dynamics that generate 24 hour rhythmicity in SCN neural activity to synaptic interactions between neural populations involved in the regulation of sleep states to the ultimately observable sleep/wake behavior of the animal. Recent advances in identifying the anatomy and physiology of circadian and sleep/wake regulatory systems provide the necessary details for constructing physiologically-based mathematical models of these systems. The three aims of this project undertake the development, analysis, and integration of mathematical models to bridge the disparate temporal and spatial scales of the problem. The project will address the following key questions: (1) the role of different sleep states, particularly rapid eye movement sleep, in the synchronization of sleep behavior with the circadian rhythm; (2) how SCN electrophysiology translates neuronal signals into molecular signals that act to shift the circadian clock; and (3) the nature of the indirect synaptic projections between the SCN and neural populations regulating sleep and wake states that govern the 24 hour rhythm in experimentally recorded rat sleep/wake patterning. The role of different sleep states on synchronization of sleep and circadian rhythms will be investigated by employing a neuronal population model of the sleep/wake regulatory network coupled to the SCN. To quantify the mathematical basis for synchronization and the characteristics of rapid eye movement sleep cycling that promote desynchronization, phase map based analytical techniques developed in coupled oscillator theory will be applied to the model. To understand how neuronal and molecular signals are integrated in SCN neurons, a Hodgkin-Huxley-type model for neurons in the suprachiasmatic nucleus will be linked to a Goodwin-oscillator-based model for the intracellular molecular clock. Model analysis will identify the mechanisms by which the actions of neuronal synaptic projections on a millisecond time scale, mediated through electrophysiology and resultant intracellular calcium dynamics, perturb the calcium-dependent 24 hour oscillations of the molecular clock. The feedforward and feedback synaptic projections between the SCN and the sleep/wake regulatory network will be investigated by fitting simulated sleep/wake patterning from neuronal population models of sleep/wake and circadian networks to 24 hour experimental rat sleep recordings. Results will provide constraints on and predictions for network structure and coupling mechanisms. Mathematically, the projects will advance techniques for multiscale modeling, provide insights into coupled oscillator systems involving both limit cycle and hysteresis loop oscillators, investigate deterministic and stochastic contributions to model dynamics, and demonstrate novel methodologies for using experimental data to constrain network models. Two graduate students and at least four undergraduate students will be trained in interdisciplinary research in mathematical neuroscience and dynamical systems through their participation in the projects. For educational outreach, a sleep/wake modeling teaching module will be developed for high school algebra classes to expose students to modeling in a personal, highly relevant context that relates to issues such as shift work, jet lag, and the well-documented sleep phase delay in teenagers.