Understanding the impact of environmental disruption in biological timing systems through signal processing.

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Project Summary/Abstract. Life on Earth evolved to take time cues from the Sun. Consequently, most or all cells in the mammalian body use genetic feedback loops to time their daily (circadian) rhythms. When a person or any mammal sees light, that winds an orchestrating circadian brain clock in the hypothalamic suprachiasmatic nucleus (SCN). The SCN in turn helps keep the myriad other tissue and endocrine rhythms in synchrony, enabling health. The modern environment is highly disruptive to this internal synchrony. Light at night from cell phones or urban light pollution, and social impositions like school start times or rotating work shifts all act as “temporal pollution,” causing loss of internal synchrony. The more severe the desynchrony, the higher the risk for a broad range of diseases, including obesity, cancer, infertility, depression and ultimately cognitive decline. Without knowing how these systems normally maintain synchrony or which systems are normally synchronized, it is hard to understand what happens in desynchrony to degrade health. This problem is complicated by the fact that some biological systems have ultradian (every few hours) and infradian (every few days) cycles in addition to circadian cycles. The hypothalamo-pituitary-adrenal axis (HPA) generates ultradian rhythms through negative feedback, but also shows a strong circadian cycle; the hypothalamo-pituitary-gonadal axis (HPG) shows the same negative feedback ultradian activity, circadian rhythmicity, and also infradian rhythms of ovulation and spermatogenesis. These two axes are regulated by the SCN. Recent work indicates that there is cross-talk between these axes, and that their hormonal outputs - corticosterone, and estradiol (in females) and testosterone (in males), respectively – work to synchronize extra-SCN tissues and behavioral rhythms of feeding and drinking (FaD). Finally, the SCN, HPA, and HPG axes all affect core body temperature (CBT), so that high temporal resolution recordings of CBT contain information about the cycling and synchrony of these systems across time scales. There are three aims to this proposal, using rats as a model system: 1) Test at high temporal resolution the effects of changes to the HPA axis, HPG axis, and SCN on CBT. 2) Use these relationships to build a model that can back-predict the state of the HPA axis, HPG axis, and SCN from a high temporal resolution CBT record of a given individual. 3) Expose rats to environmental temporal disruption in the form of a 6 h “jetlag” phase advance of the light cycle, and use the model to predict the response across these systems at 1-minute temporal resolution. This work will employ within-animal comparisons before and after surgical and pharmacological manipulations of rats whose FaD, activity, and CBT are captured continuously at 1-minute resolution. These data will be analyzed using signal-processing and machine learning to define patterns and relationships. The resulting model will allow minimally-invasive exploration of environmental disruption across physiological systems in real time. The model will be used to quantify synchrony as it is disrupted and re-emerges, identifying markers for risk or resilience, and generating hypotheses for future work into preventive strategies and treatments.