(376d) An Integrate-and-Fire Network Model to Investigate Circadian Rhythmicity in the Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN) of the hypothalamus is a multicellular system that drives daily rhythms in mammalian behavior and physiology. Although the gene regulatory network that drives daily oscillations within individual neurons is well characterized, less is known about the electrophysiology of the SCN cells and how firing rate correlates with circadian gene expression. We recently developed an integrate-and-fire neuron model to incorporate known electrophysiological properties of SCN pacemaker cells, including circadian dependent changes in membrane voltage and ion conductances. Calcium dynamics were included as the putative link between electrical firing and gene expression. By assuming autocrine response of the VIP and GABA neurotransmitters, the single cell model produced ion currents with oscillatory patterns matching experimental data both in current levels and phase relationships.

In this contribution, we develop SCN networks with the integrate-and-fire neuron model to analyze the relationship between network topology and synchronization behavior of electrical firing and gene expression. We build upon our previous work in which a connectivity scheme based on small world networks with both short and long range synaptic connections was used to explore VIP mediated coupling. The present model includes key neurotransmitters of the SCN (VIP, GABA and glutamate) that are believed mediate cell-to-cell communication and promote synchrony across the population. We show that VIP and GABA neurotransmitters play critical roles in daily oscillations of membrane excitability and gene expression, thereby affecting synchronicity across the network. Blocking various mechanisms of intracellular calcium accumulation by simulated pharmacological agents (nimodipine, IP3- and ryanodine-blockers) reproduced experimentally observed trends in firing rate dynamics and core clock gene transcription. We found that intracellular calcium regulates diverse circadian processes such as firing frequency, gene expression and system periodicity. The model predicts increased synchronization in the presence of sufficient cytosolic calcium levels and provides a novel multiscale framework which captures characteristics of the SCN at both the electrophysiological and gene regulatory levels.