Molecular-genetic Manipulation of the Suprachiasmatic Nucleus Circadian Clock

Jan 31, 2020Journal of molecular biology

Genetic Control of the Brain’s Internal Clock in the Suprachiasmatic Nucleus

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Abstract

Circadian rhythms are coordinated by the suprachiasmatic nucleus (SCN), which acts as the central timekeeper in mammals.

The SCN integrates molecular and circuit-level mechanisms that maintain circadian rhythms.
A self-sustaining feedback loop involving proteins Per, Cry, Clock, and Bmal1 is essential for the function of the circadian clock.
New techniques allow for real-time observation of clock components and their cellular effects.
Intersectional genetic manipulations reveal how SCN cells collaborate to produce a synchronized circadian signal.
Ongoing research aims to clarify the roles of specific SCN neuronal populations and astrocytes in circadian timing.

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Circadian (approximately daily) rhythms of physiology and behaviour adapt organisms to the alternating environments of day and night. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian timekeeper of mammals. The mammalian cell-autonomous circadian clock is built around a self-sustaining transcriptional-translational negative feedback loop (TTFL) in which the negative regulators Per and Cry suppress their own expression, which is driven by the positive regulators Clock and Bmal1. Importantly, such TTFL-based clocks are present in all major tissues across the organism, and the SCN is their central co-ordinator. First, we analyse SCN timekeeping at the cell-autonomous and the circuit-based levels of organisation. We consider how molecular-genetic manipulations have been used to probe cell-autonomous timing in the SCN, identifying the integral components of the clock. Second, we consider new approaches that enable real-time monitoring of the activity of these clock components and clock-driven cellular outputs. Finally, we review how intersectional genetic manipulations of the cell-autonomous clockwork can be used to determine how SCN cells interact to generate an ensemble circadian signal. Critically, it is these network-level interactions that confer on the SCN its emergent properties of robustness, light-entrained phase and precision- properties that are essential for its role as the central co-ordinator. Remaining gaps in knowledge include an understanding of how the TTFL proteins behave individually and in complexes: whether particular SCN neuronal populations act as pacemakers, and if so, by which signalling mechanisms, and finally the nature of the recently discovered role of astrocytes within the SCN network.

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Molecular-genetic Manipulation of the Suprachiasmatic Nucleus Circadian Clock

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