Ispizua, J.I., Rodriguez-Caron, M., Tassara, F.J., Kim, K.Y., Carpio-Romero, C.M., Perkins, C.I., Barzi, M., Vasquez, M.F., Hansen, C.N., Gargiulo, J., Rosato, E., de la Iglesia, H.O., Ellisman, M.H., Ceriani, M.F. (2025). Daily ultrastructural remodeling of clock neurons.  Curr. Biol. 35(23): 5808--5819.e7.

FBrf0263997

Research paper

Animals have endogenous timekeeping mechanisms to measure time and adjust their physiology to cyclical environmental changes. These biological clocks rely on neural networks to orchestrate circadian rhythmicity. Some clock neurons undergo a daily remodeling of their morphology-known as circadian structural plasticity-that is expected to impact their connectivity and function. This process remains poorly defined at the subcellular level, preventing a full understanding of how it relates to other cyclical properties. In this study, we generated 3D electron microscopy reconstructions of adult Drosophila brains at three key time points to examine ultrastructural changes in the terminals of core clock neurons. We found that neuronal varicosities are the organizational units underlying these structural changes, as they contain the functional elements required for neuronal communication (active zones and dense-core vesicles) and for their metabolic support (mitochondria). Varicosities appear to change in number during the day-night cycle while exhibiting differences in the number of active zones, in the accumulation of dense-core vesicles, both full and fused, and in the number, shape, and size of the mitochondria. These results suggest an interplay between structural and functional plasticity that was not appreciated to date. We propose that circadian plasticity of presynaptic varicosities modulates the influence of specific clock neurons onto the circadian network. Given the conservation across timekeeping mechanisms, ultrastructural changes might underlie circadian shifts in neuronal connectivity across species.