Circadian Rhythm Generation and Entrainment in Astrocytes

Abstract

In mammals, the master circadian pacemaker is considered the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of a heterogeneous population of neurons and relatively understudied glia. We investigated whether glia, like neurons, rhythmically express circadian genes. We generated pure cultures of cortical astrocytes from Period2::luciferase (Per2::luc) knock-in mice and Period1::luciferase (Per1::luc) transgenic rats and recorded bioluminescence as a real-time reporter of gene activity. We found that rat Per1::luc and mouse Per2::luc astroglia express circadian rhythms with a genetically determined period. These rhythms damped out after several days but were reinitiated by a variety of treatments, including a full volume exchange of the medium. If cultures were treated before damping out, the phase of Per1::luc rhythmicity was shifted, depending on the time of the pulse relative to the peak of Per1 expression. Glial rhythms entrained to daily 1.5°C temperature cycles and were significantly sustained when cocultured with explants of the adult SCN but not with cortical explants. Thus, multiple signals, including a diffusible factor(s) from the SCN, are sufficient to either entrain or restart circadian oscillations in cortical glia.

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…Per1 is crucial for the regulation of circadian activity and has been shown to be involved in the effects of drugs of abuse (Abarca et al, 2002;Falcon and McClung, 2009). The oscillatory pattern of Per1 expression has been demonstrated in ex vivo astrocytes (Prolo et al, 2005), but the exact role of the clock genes in astrocytes is unknown. The group of genes downregulated by dexamethasone contains four genes that are related to cell differentiation (Wnt7a, Wnt7b, Sox2, and Trib2).…”

Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons

“…Some of the cells that did not express VIP or AVP in the low-density cultures may not have been neurons. For example, astrocytes can express circadian rhythms in PER2 (20) but were rare in these cultures according to phase contrast imaging. Importantly, the proportion of circadian cells was similar when comparing PER2::LUC and firing rate data, suggesting that the data come from neurons.…”

The role of clock genes and rhythmicity in the liver

“…Interestingly, circadian changes in environmental temperatures were able to phase shift gene expression in the liver but not in the SCN. In addition, astrocytes have been shown to be entrainable by temperature cycles of 1.5°C (Prolo et al, 2005). The resistance of the SCN but not peripheral clocks to temperature changes may originate from network interactions inside the SCN.…”