Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

Abstract

The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcription-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Na þ drive and nighttime K þ drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep -wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness.W e wake and sleep each day. Hormones reach peak plasma levels at specified times, for example cortisol peaks in the early morning. These, and many other physiological and behavioral, daily rhythms depend on an internal circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. Prior reviews have provided excellent summaries of research progress in the location and function of this body clock (Weaver 1998). This work focuses on recent advances in our understanding of the genetic basis for cell-autonomous generation of circadian time, and how cells within the SCN synchronize their daily rhythms across the circuit to produce a coherent oscillation in neuronal activity. It is these circuit-level emergent properties of the SCN that ultimately direct daily behaviors such as wake and sleep.

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

“…The SCN is the “master clock” of the body and serves to synchronize peripheral clocks to the light:dark cycle, creating coherent organismal circadian rhythms in behavior, physiology, and cellular function. The SCN receives direct neuronal input from the retina, and exposure to light causes induction of clock gene expression and synchronizes the core circadian machinery in pacemaker neurons in the SCN [10, 11]. Circuitry within the SCN integrates this signal, resulting in robust circadian oscillations in neuronal firing.…”

Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling

“…This robust pacemaking is widely viewed as a product of neuropeptidergic inter-neuronal signaling across the SCN circuit (Liu et al., 2007, Maywood et al., 2011). Recently, the roles of different neuronal subpopulations in the SCN have been assessed by selective genetic manipulations (see Herzog et al., 2017). Collectively, these data indicate that neurons in the dorsal SCN, mainly expressing arginine-vasopressin (AVP), are pacemaker cells, capable of imposing their intrinsic periodicity to mouse behavior, whereas neurons expressing vasoactive intestinal peptide (VIP) in the ventral region are important for light entrainment and internal synchronization.…”

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

“…These proteins drive the transcription of several clock-related genes including Period (Per1/2/3), Cryptochrome (Cry1/2), REV-ERB proteins (Nr1d1/Nr1d2 encode REV-ERBα/REV-ERBβ), and retinoic acid receptor-related orphan receptors (e.g., Rora). Of these, REV-ERBα and β transcriptionally repress Bmal1 by binding to the RORE cis-element in its promoter region (Herzog, Hermanstyne, Smyllie, & Hastings, 2017) and connect the circadian system to macrophage-driven inflammation (Gibbs et al, 2012;Griffin et al, 2019;Pariollaud et al, 2018). Rev-Erbα/β are also nuclear receptors which function as transcriptional repressors and exert a variety of biological functions (Everett & Lazar, 2014;Lam et al, 2013;Woldt et al, 2013).…”