We live in an approximately 24-hour world and circadian rhythms have evolved to adapt organisms to the opportunities presented by Earth’s 24-hour cycle of light and dark. A “master clock” located in the suprachiasmatic nucleus (SCN) of the brain orchestrates daily rhythms in all manner of behavioral, endocrine, metabolic, autonomic, and homeostatic systems in our bodies. The SCN is comprised of about 20,000 neurons and about one third as many astroglia. How can so few neurons and astroglia guide so many rhythms? How do neurons time out an interval as long as a day? The answers are a case study in understanding how genes within cells, and cells within circuits, function together to perform complex activities and optimize bodily functions. While individual clock cells are found in virtually all bodily tissues, the unique connectome of the SCN, its specialized afferent inputs from the retinohypothalamic tract, and its neural and humoral outputs enable its “babel” of neuronal types to synchronize their activity and signal time to the rest of the body.
At the molecular-cellular level, circadian rhythms are regulated by a 24-hour transcriptional–translational feedback loop. At the SCN tissue level, individual SCN neurons coordinate their gene expression and electrical activity, working together in circuits that sustain coherent rhythms. The SCN has many distinct cell types based on their neurotransmitters, neuropeptides, and afferent and efferent connections. There has been much progress in unraveling the dynamic network organization that underlies the SCN network’s communications. Though the precise anatomical connections underlying interneuronal communication in the SCN are not completely understood, key signaling mechanisms that sustain the SCN’s intrinsic rhythmicity have been tackled using intersectional genomic tools. Transgenic animals that permit the visualization of clock gene–protein expression have enabled analysis of SCN network activity over time. Availability of animals bearing mutations in clock genes or proteins enable the determination of changes within neurons, among neurons in networks, and their impact on behavior. The use of continuous readouts of circadian activity that track behavior, or clock gene expression, or electrical activity changes over time, within an SCN or a single neuron, leads the way to unraveling mechanisms sustaining the circadian timing system. Because the results of circadian studies generate huge amounts of data, the entry of mathematical modelers and statisticians into the field has begun to yield useful and testable predictions on how these multiplexed systems work to adapt to our 24-hour world.
calmodulin inhibitors phase shift circadian rhythms of suprachiasmatic nucleus neuron activity in rat hypothalamic slices