Professor Michael Henson, a faculty member in the Chemical Engineering Department at the University of Massachusetts Amherst, is the principal investigator for a three-university collaborative project, which involves creating mathematical models of “circadian rhythm” generation to better understand sleep disorders and other diseases triggered by the malfunction of this 24-hour “body clock” in humans. The research is being supported by a very significant, four-year, $1,809,385 grant from the National Institutes of Health (NIH).
Henson’s NIH research project is entitled “Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling,” and the co-PIs are Erik Herzog of Washington University and Yannis Kevrekidis of Princeton University. This latest NIH grant follows similar, four-year, $950,000 grants from the NIH, issued in 2006 and 2012, to study the 24-hour circadian rhythm in human beings.
Henson’s models simulate how some 20,000 neurons in the suprachiasmatic nucleus (SCN) region of the hypothalamus, located in the brain stem, synchronize with each other to create the circadian rhythm that helps control sleep patterns in humans and other mammals.
A circadian rhythm is a 24-hour cycle in biochemical, physiological, or behavioral processes controlled by the SCN. Although such body clocks are built-in and self-sustaining in humans, they are influenced by external cues, the primary one being daylight.
“If you’ve ever traveled overseas,” Henson said about his research, “you can certainly understand what we’re studying. Your body clock is thrown out of sync with the change in daylight hours you are used to, so jet lag sets in.”
The NIH project’s findings could have far-reaching impacts on studies of sleep disorders, jet lag, and other behavior related to the body clock.
The goal of Henson’s current NIH project is to combine modeling, experiment, and computation to unravel the effects of variable light patterns on the network topology, synchronization behavior, and entrainment properties of the SCN. Henson said that the SCN represents an ideal model system for studying biological network design and behavior due to accumulating data on individual SCN neurons and their interactions.
Experimental studies have shown that SCN intercellular communication is primarily mediated by two neurotransmitters: vasoactive intestinal peptide (VIP) and gamma-aminobutyric acid (GABA). While VIP is well established as an essential synchronizing agent, the role of GABA with respect to its inhibitory/excitatory, day/night, synchronizing, and entrainment effects remains controversial.
As the NIH abstract for Henson’s new grant said, “The research focuses on GABA signaling because its role in the SCN is prominent, not well understood, and recent advances by the three participating investigators will enable a complete and careful dissection of the role of this common neurotransmitter with synapse-level resolution across large arrays of circadian neurons.”
Henson’s role in the project is to take data about the neurons, generated through biology experiments by his collaborators, and build models that accurately simulate how the 20,000 neurons of the SCN act as a synchronized system to produce the circadian clock. The process requires Henson’s team to analyze the experimental data, create individual neuron models with them, then incorporate these individual models in complex system models of how all the neurons work together.
Henson’s collaborator at Washington University is circadian biologist Herzog, whose main hypothesis is that VIP, which is secreted by neuron cells, works to set up communication among the neurons in the SCN.
“The molecular-level mathematical models we develop on the computer are based on this hypothesis,” said Henson, “that VIP is the main mechanism by which these 20,000 neurons communicate. If you have all these cells doing their own thing, then they’re not going to generate a coherent overall circadian rhythm.”
As Henson explained, when his computer models are “robust enough,” then they can be used to tackle such important issues as sleep disorders related to circadian rhythm, the most effective way to recover from jet lag, and how to adjust the body clock in soldiers, airline pilots, surgeons, nurses, and other professionals so they can stay alert when awake for long periods of time.
The research has the potential to be highly transformative by both advancing the multiscale modeling of coupled oscillators/complex networks and by fundamentally changing the human understanding of GABA signaling in circadian timekeeping and potentially in other brain regions. (January 2017)