Rocking all night to circadian rhythms

Circadian rhythms dictate our day and night motor activity, but how do these cycles interact and operate?

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Image Credit: Eugenia Loli

FROM ASLEEP TO awake: a transition that is by no means random - circadian rhythms are internal processes which regulate our activity and rest on a roughly 24hour spectrum.

These circadian rhythms are subject to change dependent on present environmental stimuli,such as light, temperature and redox cycles, allowing organisms to adapt to their surroundings specifically on a day-by-day basis.The clock is largely conditioned by the light to dark cycles year round.Even the blind mole rat is not exempt; despite lacking eyes that can form images, photoreceptors detect presence or absence of light to influence their body clock. Light and dark cycles affect not only mammals but also plants, fungi and cyanobacteria. Light acts asa ‘reset button’ for the body clock,but threshold is dependent on the organism, usually being lowest for nocturnal rodents.

In flies, the body clock is regulated by 75 pairs of neurones.These are clustered, with each cluster’s activity being staggered to peak in activity at certain points throughout the 24 hour rhythm.We have known for some time that distinct cells in clusters regulate dawn and dusk motor activity, but a recent paper by Xitong Liang has now identified one of the downstream targets of these neurones and how they are regulated. At the centre of this research are ellipsoid body “ringneurones” (EB-RNs) - a diverse group of cells associated with sleep and locomotor activity. They became the focus of this research when in-creased calcium influx was detect-ed in these neurones, corresponding to dawn and dusk locomotor activity.

It was hypothesised that EB-RNs and their activity correlated with dusk and dawn behaviour which seemed promising in up-stream candidates. Other papers produced earlier this year support this hypothesis. Experimentally altered body clocks which “selectively phase-advances” their morning and evening neural activity peaks” was again correlated with EB-RN activity, showing the same adjustment to their pattern that the body clock was subjected to.

Liang enquired into how the circadian centre is connected to the EB-RNs while lacking EB projections. What is linking the two? And does it provide a piece of the body clock puzzle? They reasoned that the activation of EBs relied on signalling via dopamine molecules, as the activation of these dopamine neurones initiates loco-motion in other areas of the brain. When the activity of these dopa-mine neurones were analysed they also correlated with changes in body clock, thus determining that they are affected by the circadian centre and directly synapse to theEB-RNs.

Furthermore, the research has highlighted the distinction between M-cells’ and ‘E-cells,which make up part of the molecular clock on a neural level, each one’s activity peaking at morning and evening respectively. Liang’s research has provided strong evidence that M and E cells contribute to circadian rhythms in loco-motor activity by independently acting on EB-RNs via dopamine signalling. Not only have we gained a greater understanding of this dawn and dusk loco-motion, other papers have generated evidence that there is cross-talk between these distinctM and E cell path-ways in the form of interaction between sleep and activity promoting cascades. Sleep-promoting EB-RNs may inhibit dopamine neurones to reduce sensory activity during sleep. Liang has suggested that these findings may be down to EB-RNs playing a role in sleep homeostasis by recording ‘quantity and quality of prior waking experiences’ to then alter the regulation of the body clock.These are huge advances in improving understanding, but there is still more to do. There are other downstream targets and M and E cells, that contribute to the balance between rest and activity are, yet to be investigated.In broader terms, the functional variability in clock neurones and their cross-talk means this is no simple task.

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