Regulation and function of extra‐SCN circadian oscillators in the brain

Abstract

Most organisms evolved endogenous, so called circadian clocks as internal timekeeping mechanisms allowing them to adapt to recurring changes in environmental demands brought about by 24-hour rhythms such as the light-dark cycle, temperature variations or changes in humidity. The mammalian circadian clock system is based on cellular oscillators found in all tissues of the body that are organized in a hierarchical fashion. A master pacemaker located in the suprachiasmatic nucleus (SCN) synchronizes peripheral tissue clocks and extra-SCN oscillators in the brain with each other and with external time. Different time cues (so called Zeitgebers) such as light, food intake, activity and hormonal signals reset the clock system through the SCN or by direct action at the tissue clock level. While most studies on non-SCN clocks so far have focused on peripheral tissues, several extra-SCN central oscillators were characterized in terms of circadian rhythm regulation and output. Some of them are directly innervated by the SCN pacemaker, while others receive indirect input from the SCN via other neural circuits or extra-brain structures. The specific physiological function of these non-SCN brain oscillators as well as their role in the regulation of the circadian clock network remains understudied. In this review we summarize our current knowledge about the regulation and function of extra-SCN circadian oscillators in different brain regions and devise experimental approaches enabling us to unravel the organization of the circadian clock network in the central nervous system. K E Y W O R D S brain, circadian clock, clock gene, CNS, entrainment 2 of 14 | BEGEMANN Et Al.major depression or cardiovascular disorders are promoted by chronodisruption, that is, the perturbation of internal clock function or of the alignment of these clocks with external time. 4 Besides shift work, other chronodisruptive factors are sleep curtailment, high-energy diets or mistimed eating patterns, and nocturnal light pollution. 5,6 Resetting stimuli (eg light)Resetting stimuli (eg PUFAs) Resetting stimuli (eg NO/CO) RORE D-box E-box CLOCK BMAL1 REV-ERBs RORs DBP NFIL3 PERs CRYs CCGsHow to cite this article: Begemann K, Neumann A-M, Oster H. Regulation and function of extra-SCN circadian oscillators in the brain. Acta Physiol.

Circadian Rhythms of the Hypothalamus: From Function to Physiology

“…Hypothalamic extra-SCN oscillators are now recognized to play integral roles in essential physiological functions such as eating, sleep-wake cycles, energy metabolism and thermoregulation [43][44][45][46]. One example of diurnal activity considered to be controlled independently of the SCN is food-anticipatory activity (FAA), which can persist in spite of SCN ablation [47].…”

Orexin A excites the rat olivary pretectal nucleus via OX2 receptor in a daily manner

“…However, recent evidence strongly suggests that circadian control of many physiological processes must be devolved to local clocks localised in several brain structures and peripheral tissues (Abe et al, 2002;Begemann et al, 2020;Paul et al, 2020). Recently, we have reported circadian timekeeping properties also in the subcortical visual system outside of the SCN (Chrobok et al, 2021a(Chrobok et al, , 2021b.…”

“…In mammals, the master clock is localised in the suprachiasmatic nucleus (SCN) of the hypothalamus (Hastings et al, 2019(Hastings et al, , 2018Takahashi, 2017). However, recent advances show several other brain areas and peripheral tissues to exhibit autonomous or semi-autonomous circadian rhythms (Begemann et al, 2020;Guilding and Piggins, 2007;Paul et al, 2020). Moreover, the orexinergic system of the lateral hypothalamus has been schematised to act as the hands of the clock; due to its reciprocal connection with the SCN orexins deliver arousal for a plethora of brain sites in a circadian manner (Azeez et al, 2018;Belle et al, 2014;Marston et al, 2008).…”

Daily orexinergic modulation of the rat superficial layers of the superior colliculus – implications for intrinsic clock activities in the visual system

“…However, accumulating evidence describes multiple extra-SCN brain oscillators, which autonomously or semi-autonomously express clock genes to coordinate their processes in a day-to-night changing manner [9,11]. In our study, we describe for the first time the daily (under LD) and circadian (under Our MEA recordings unravelled the daily variation in the spontaneous neuronal activity in the superficial layers of the SC, exhibiting a pronounced decrease at the beginning of dark phase, compared to the high levels of SUA throughout the day.…”

“…As the central circadian clock, the suprachiasmatic nucleus of the hypothalamus (SCN) reciprocally connects with the orexinergic system and directs the profound day-to-night changes, orexins have been hypothesised to act as hands of the clock [5][6][7][8]. However, new findings question the omnipotent role of the SCN in the circadian control of the brain physiology and function, with several neuronal centres rhythmically expressing clock genes independently from the central clock [9][10][11]. The extent to which these local circadian clocks interact and play a role in the brain physiology is now an active area of research.…”