Circadian regulation of membrane physiology in neural oscillators throughout the brain

Abstract

Twenty‐four‐hour rhythmicity in physiology and behavior are driven by changes in neurophysiological activity that vary across the light–dark and rest‐activity cycle. Although this neural code is most prominent in neurons of the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, there are many other regions in the brain where region‐specific function and behavioral rhythmicity may be encoded by changes in electrical properties of those neurons. In this review, we explore the existing evidence for molecular clocks and/or neurophysiological rhythms (i.e., 24 hr) in brain regions outside the SCN. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators. For example, the cerebellum expresses rhythmicity in over 2,000 gene transcripts, and yet we know very little about how circadian regulation drives 24‐hr changes in the neural coding responsible for motor coordination. Finally, we conclude with a discussion of how our understanding of circadian regulation of electrical properties may yield insight into disease mechanisms which may lead to novel chronotherapeutic strategies in the future.

Keeping time in the lamina terminalis: Novel oscillator properties of forebrain sensory circumventricular organs

“…However, unlike the SCN, cells of the OVLT and SFO lack precision in their periodicities and cannot maintain synchronized rhythms. Clock gene rhythms in extra-SCN brain areas are often less robust than those of the master pacemaker, 9,42 thus it is surprising that whole area SFO oscillations were similar in relative amplitude over the first 4 days to the SCN. Circadian rhythms in the OVLT have previously been demonstrated in clock gene bioluminescence [25][26][27] and Per3.…”

“…8,10 In comparison to the SCN, single-cell oscillators in the SFO were less synchronized and displayed greater variability in their individual cellular periods, while the time of peak phase and average period of cells in these structures did not differ. Clock gene rhythms in extra-SCN brain areas are often less robust than those of the master pacemaker, 9,42 thus it is surprising that whole area SFO oscillations were similar in relative amplitude over the first 4 days to the SCN. It is not clear why rhythms in the SFO are robust, but since this structure is enriched in the nonneuronal glia cells 32,43 and because astrocytes are important for circadian timekeeping in the SCN [44][45][46] , this network of nonneuronal cells may imbue the SFO with enhanced capability of self-sustained circadian timekeeping.…”

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

“…The retina was the first neuronal tissue outside the SCN to be shown to have endogenous, autonomous circadian rhythms of melatonin synthesis in vitro . Since then, by studying rhythms in expression of clock genes and electrical activity, a variety of regions all across the brain spanning from tel‐ to metencephalon were found to oscillate . Real‐time bioluminescence recordings of clock gene reporters in different tissues allowed to investigate the sustainability of circadian oscillators when disconnected from the body.…”

“…Circadian gene expression is found in regions of the hindbrain and thalamus. For a thorough discussion see the recent review from Paul et al Taken together, it becomes clear that circadian clocks are distributed throughout the brain. Most of these oscillators are strongly dependent on the SCN.…”

Circadian rhythmicity and the community of clockworkers

“…This work suggests a link to understanding the influence of redox on memory formation—a key function of the hippocampus. There is substantial evidence that there are molecular clocks in brain regions outside the SCN and it is important to understand how these transcriptional‐translational clock gene rhythms are related to changes in the neurophysiology at different times of the day (Paul et al, ). The review provides a compendium of the evidence for extra‐SCN oscillations, highlighting what is known of functions in different brain regions and where more work is needed.…”