The Biological Clock is ticking ex vivo and in silico

Abstract

Daily rhythms in behavior and physiology such as the sleep/wake cycle and hormonal rhythms are regulated by a 24-hour (circadian) clock in the brain called the suprachiasmatic nucleus (SCN). The output of the SCN is an emergent property of coupled oscillators. The SCN consists of thousands of neurons each of which is an autonomous circadian oscillator. They are normally coupled to generate the output that regulates circadian rhythms throughout the body. In the SCN, as in other parts of the brain, neural connectivity arises during development to produce the specific circuitry essential for a particular function. As one approach to understanding neural circuitry in the SCN we are studying the development of SCN rhythms with continuous, real-time measurement of gene expression linked to bioluminescence. We are measuring bioluminescence from embryonic mouse SCN maintained in culture (ex vivo) for several days. We hypothesize that SCN rhythms emerge as the coupling among its cells develops. To test this, we have implemented an established model of SCN structure and function and are comparing the rhythms we measure to those generated by model-driven simulations (in silico). In some instances, the rhythms expressed by the developing SCN have unexpected, complex features. The model allows us to identify processes or conditions that might account for these features, leading to new, testable hypotheses about how dynamic network interactions relate to the functional output of the clock. We will present examples of the SCN rhythms we have measured and will compare them to rhythms generated by the model.