Misalignment of circadian clocks with 24 h environmental cycles adversely impacts brain function including sleep, cognition and performance. While the mechanisms of molecular timekeeping have been revealed, the field lacks a comprehensive understanding of how oscillating clock genes control daily rhythms of firing rates in clock neurons, how these clock neurons connect with each other to produce appropriately timed behavior, and how different sensory cues such as light, nutrients and temperature are integrated to ensure appropriate alignment of the clock to the 24 h environment. To address this problem, experimental approaches will be integrated at multiple levels with novel mathematical tools. Specifically, optical imaging will be used to assess neuronal excitability, synaptic connectivity, and sensitivity to photic and thermal inputs will be used of a model circadian neural network. To integrate multi-tiered experimental data, new data assimilation techniques will be employed to infer mechanistic (e.g., Hodgkin-Huxley-type) models from time course data. Several aspects of this approach will enable us to develop novel models. First, among all behaviorally relevant neural circuits the molecular understanding of the core clock components is highly advanced. Second, the system is highly conserved in all animals from the fruit fly Drosophila to humans. Third, the neural networks of Drosophila that drive circadian behavior are comprised of only 100 neurons separated into identifiable groups, allowing a comprehensive understanding of network structure and function. Given this baseline data as well as the wealth of experimental and modeling approaches to be developed, understanding how multiple sensory modalities are integrated to ensure the appropriate alignment of internal clocks to environmental cycles is within reach. This not only impacts the understanding of circadian clocks but also develops a novel experimental and computational algorithm that could be applied to the understanding of any aspect of behavior or performance. These studies may also address fundamental laws of biology that explain the quantitative relationship across levels (e.g., subcellular to neuronal networks) as well as temporal scales (e.g. hours for circadian timing and seconds for firing rates). In addition, this work is highly relevant to the ARO mission given the role of circadian misalignment in disrupting the health and performance of pilots who fly across several time zones and soldiers who must perform at night against their clock. Understanding how the system works in general and especially how environmental cues can adjust the phase of the clock will be important in developing countermeasures for jet lag and shift work.
|Effective start/end date||10/1/16 → 9/30/20|
- Army Research Office (W911NF-16-1-0584 P000010)