Mathematical modeling of circadian rhythm generation and synchronization in mammalian cells

• Main Author: Vasalou, Christina
• Language: ENG
• Published: ScholarWorks@UMass Amherst 2011
• Subjects: Neurosciences|Chemical engineering
• Online Access: https://scholarworks.umass.edu/dissertations/AAI3465228

Circadian rhythms are ∼24 hour cycles in behavioral and physiological responses observed in a wide range of organisms. The role of this central clock lies in its ability to recognize different environmental stimuli and adapt the behavior of organisms accordingly. This response is critical for an organism's survival and evolution as it allows for the anticipation of environmental cues. The circadian pacemaker of mammalian organisms is located in the brain region of the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN produces self-sustained oscillations and further controls a number of metabolic processes across distinct organs. This thesis has focused on the mathematical modeling of the SCN to investigate mechanisms responsible for the generation and synchronization of daily signals across the circadian network. For this purpose, we developed several multicellular models of the mammalian circadian clock characterized by a high degree of heterogeneity with respect to single cell periodicity and behavior (intrinsic and driven oscillators), neurotransmitter release (vasoactive intestinal peptide (VIP), γ-aminobutyric acid (GABA) and glutamate synthesis) and spatial organization (long range versus short range connectivity). A firing rate code model was further developed to incorporate known electrophysiological properties of SCN pacemakers that give rise to the electrical firing of individual neurons. In this model, daily changes in ion conductances, ion concentrations and membrane properties (such as membrane resistance) were integrated to produce circadian changes in the action potential frequency of SCN neurons. Intracellular signaling pathways, initiated by cytosolic calcium and VIP, were also included as the putative link between electrical firing and gene expression. The developed model predicted a direct relationship between firing frequency and gene expression amplitudes, demonstrated the importance of intracellular pathways for circadian behavior and synchrony and provided a novel multiscale framework which captured characteristics of the SCN at both the electrophysiological and gene regulatory levels. We further attempted to mimic the structural organization of the SCN and utilize experimentally derived connectivity schemes to simulate the SCN’s ventrolateral and dorsomedial subdivisions. The model predicted that sufficient connectivity between the two separate regions, associated with distinct circadian functions, was responsible for the expression of sustained circadian behavior.