Factors of Circadian Rhythm Clocks

          We had the opportunity to have Dan Cavanaugh give a seminar on the clock neuron regulation in Drosophila, also known as fruit flies. His and his colleagues work can be found in the research paper titled, “The cell-intrinsic circadian clock is dispensable for lateral posterior clock neuron regulation of Drosophila rest-activity rhythms” and goes in detail on the effects LPN’s or lateral posterior clock neurons have on the regulation of circadian rhythms. Due to recent developments, a genetic modification tool called split-Gal4 has allowed for extremely specific modification of neuronal cells, to the point where certain clock neurons can be modified. Using this technique, they were able to modify the clocks inside specific LPNs knocking out certain genes responsible for the clock. Along with being able to modify the LPNs they were also able to completely silence them using Kir2.1 which floods the cells with potassium, preventing action potentials from being fired. From these scenarios, they found that LPNs output are critical to do their job, silencing from Kir2.1 had weakened the circadian rhythm in those flies, but not completely disrupted the core circadian rhythm . They also found that the LPN’s internal clock being removed doesn’t have a massive effect on the LPNs function, meaning LPNs still regulate circadian rhythms without their internal clocks. 

A different research paper named, “Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals” also has valuable insight on how these circadian rhythms may keep their clock or timing correct. The researchers here mutated mice, modifying the promoters for Bmal1, a clock gene. The findings showed that despite losing the Bmal1 clock, proved by a constant level of Bmal1 RNA instead of a varying amount throughout the day, the mice still kept their circadian rhythm clocks, similar to how Drosophila kept their clocks despite having Gal4 knockout clock genes. In this case this Bmal1 knockout reduced the stability of the circadian clock system, but did not completely take it down. Similar to the changes seen in Drosophila, reduced accuracy, but the main clock is still kept. 

Both of these articles discussed what had happened when certain clock genes were removed from their respective subjects, or their signals were blocked. In both cases the core circadian rhythms were kept with a small decrease in system stability or less fine tuning of the circadian rhythm. This suggests one of two things, that the core circadian rhythm comes from a different clock gene, or that, the core circadian rhythm is composed of several clock genes across several types of cells in the brain, so even when there’s a defect in one, that doesn’t completely remove the circadian rhythm for that animal. It’s not currently clear how the main circadian clock and individual clocks within cells communicate, influence, or construct each other, but these research papers provide some insight, that the core circadian rhythm is most likely not taken from just one type of cell’s clock, and is most likely comprised of several different cells with different responsibilities. 

Abe, Yasuko, et al. “Rhythmic Transcription of Bmal1 Stabilizes the Circadian Timekeeping System in Mammals.” Zenodo (CERN European Organization for Nuclear Research), 3 May 2022, https://doi.org/10.5281/zenodo.6512360.

Guerrero, Charlene Y P, et al. “The Cell-Intrinsic Circadian Clock Is Dispensable for Lateral Posterior Clock Neuron Regulation of Drosophila Rest-Activity Rhythms.” Neurobiology of Sleep and Circadian Rhythms, vol. 18, 2025, p. 100124, pubmed.ncbi.nlm.nih.gov/40386580/, https://doi.org/10.1016/j.nbscr.2025.100124.