GABAergic mechanisms in the suprachiasmatic nucleus that influence circadian rhythm.

The mammalian central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN contains multiple circadian oscillators which synchronize with each other via several neurotransmitters. Importantly, an inhibitory neurotransmitter, γ-amino butyric acid (GABA), is expressed in almost all SCN neurons. In this review, we discuss how GABA influences circadian rhythms in the SCN. Excitatory and inhibitory effects of GABA may depend on intracellular Cl- concentration, in which several factors such as day-length, time of day, development, and region in the SCN may be involved. GABA also mediates oscillatory coupling of the circadian rhythms in the SCN. Recent genetic approaches reveal that GABA refines circadian output rhythms, but not circadian oscillations in the SCN. Since several efferent projections of the SCN have been suggested, GABA might work downstream of neuronal pathways from the SCN which regulate the temporal order of physiology and behavior.

The mammalian circadian system: a hierarchical multi-oscillator structure for generating circadian rhythm.

The circadian nature of physiology and behavior is regulated by a circadian clock that generates intrinsic rhythms with a periodicity of approximately 24 h. The mammalian circadian system is composed of a hierarchical multi-oscillator structure, with the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus regulating the peripheral clocks found throughout the body. In the past two decades, key clock genes have been discovered in mammals and shown to be interlocked in transcriptional and translational feedback loops. At the cellular level, each cell is governed by its own independent clock; and yet, these cellular circadian clocks in the SCN form regional oscillators that are further coupled to one another to generate a single rhythm for the tissue. The oscillatory coupling within and between the regional oscillators appears to be critical for the extraordinary stability and the wide range of adaptability of the circadian clock, the mechanism of which is now being elucidated with newly advanced molecular tools.

Deconstructing Circadian Rhythmicity with Models and Manipulations.

A master brain clock, localized to the hypothalamic suprachiasmatic nucleus (SCN), coordinates daily rhythms of physiology and behavior. Within the SCN, interconnected individual neurons are oscillators that, as an ensemble, function to send a coherent timing signal to the brain and body. However, individually, these neurons display different amplitudes, periods, and phases of oscillation. The dynamic properties of the SCN have been characterized over several spatial levels of analysis, from proteins to cells to tissues, and over several temporal ranges, from milliseconds to weeks. Modeling tools guide empirical research in this complex and multiscale spatiotemporal environment. Given that the SCN is a prototypical example of oscillating neural systems, principles of its organization hold promise as general prototypes of rhythms in other frequencies.

Human blood metabolite timetable indicates internal body time.

A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, molecular-timetable method with human blood enables highly optimized and personalized medicine.

Molecular-timetable methods for detection of body time and rhythm disorders from single-time-point genome-wide expression profiles.

Detection of individual body time (BT) via a single-time-point assay has been a longstanding unfulfilled dream in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To achieve this dream, we created a "molecular timetable" composed of >100 "time-indicating genes," whose gene expression levels can represent internal BT. Here we describe a robust method called the "molecular-timetable method" for BT detection from a single-time-point expression profile. The power of this method is demonstrated by the sensitive and accurate detection of BT and the sensitive diagnosis of rhythm disorders. These results demonstrate the feasibility of BT detection based on single-time-point sampling, suggest the potential for expression-based diagnosis of rhythm disorders, and may translate functional genomics into chronotherapy and personalized medicine.