Mechanisms of Circadian Entrainment and Plasticity

A fundamental question in biology and medicine is - how do genes and gene networks give rise to physiology, function, and behavior? The brain’s endogenous 24-hour timing mechanism, or circadian clock, is uniquely advantageous for studying the molecular physiology of neural function and the genes-to-behavior problem because both the neural substrates and gene networks are highly defined, particularly in two molecular genetic model organisms – mice and fruit flies. The neural networks that time circadian rhythms in physiology and behavior are located within the suprachiasmatic nuclei (SCN) of the hypothalamus in mammals and in neuron clusters in the dorsal and lateral Drosophila brain. Circadian clock neurons in mice and flies exhibit self- sustained circadian rhythms in spontaneous spike frequency driven by networks of clock genes organized in transcription/translation negative feedback loops (TTFLs) that generate ca. 24-hour rhythms. While much is known about the genes, neurons, and synapses that are critical for the generation of circadian rhythms, there are key gaps in our knowledge regarding the mechanisms of synchronization of these internal clocks to local environmental time - the process of entrainment, and the striking pacemaker plasticity entrainment induces. Entrainment to different seasonal day lengths (photoperiods), or even a single clock reset by a light pulse, can enduringly alter the intrinsic waveform, period, and resetting properties of circadian clocks. The long-term plasticity of circadian clocks in response to entraining light cycles is thought to be critical for stable alignment to changing seasonal photoperiods, and likely contributes to disorders of desynchrony, SCN changes in aging, and to discordance between SCN and peripheral tissue clocks. An overarching interest of my laboratory is to elucidate fundamental cellular and molecular mechanisms of circadian entrainment and clock plasticity. To this end we have developed novel methods for direct observation and manipulation of clock entrainment dynamics at the molecular, cellular, and neural network levels. Our approach, which we call EX vivo CIrcadian Timing and Entrainment (EXCITE), combines optogenetic manipulation of clock neuron electrical activity with real-time bioluminescence reporting of clock gene activation and rhythms. In addition, to further understanding of molecular genetic mechanisms of entrainment we have recently elucidated candidate transcriptomic mechanisms of SCN photoperiod-induced plasticity, as well as explored the evolution of human clock genes in the form of genomic introgressions from Neanderthals and Denisovians as adaptions to high latitude seasonal light cycles. We have also extended our studies of entrainment to the honey bee clock which has a unique molecular structure. Our overall plan for the next five years is to combine these innovative findings and approaches to address critical gaps in knowledge regarding clock entrainment and light-induced clock plasticity. Project Number: 5R35GM156224-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: DOUGLAS MCMAHON | Institution: VANDERBILT UNIVERSITY, Nashville, TN | Award Amount: $435,875 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - D Study Section[MRAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11378258