Elucidating the fundamental cellular and molecular mechanisms of circadian entrainment, clock plasticity, and downstream effects of clock synchronization on behavior and physiology.
Why biological clocks?
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.
Graphic created by Suil Kim.
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, the striking pacemaker plasticity entrainment induces, and the downstream effects on brain circuits controlling mood, motivation and behavior.