Notch canonical activity in a subset of glial cells regulates short-term memory in Drosophila

Notch is a transmembrane receptor expressed at the cell surface that mediates transcriptional responses upon binding to its ligands, in a variety of contexts. Evolutionarily conserved, Notch plays a key role in numerous cell fate decisions during development and is also required in post-mitotic brain neurons for the consolidation of long-term memory and long-term habituation. Notch signaling is highly expressed in glial cells, where it plays a key role in regulating their development and proliferation. More recently, a Notch-dependent neuroglial pathway has been implicated in modulating the susceptibility of short-term memory to sleep deprivation in Drosophila . In this study, we demonstrate that canonical Notch signaling in glia— mediated by the Delta ligand and the transcription factor Suppressor of Hairless—is activated in a subset of cortex and ensheathing glial cells. This signaling is essential for the formation of short-term memory in the aversive phototaxic suppression assay, which is sensitive to sleep deprivation. Dopaminergic transmission is known to be required for this type of learning and is negatively impacted by sleep deprivation, suggesting a possible interaction between Notch and dopamine pathways. Supporting this idea, we find that modulating dopaminergic transmission downregulates canonical Notch activity in glial cells. Conversely, activating Notch signaling in glia near dopaminergic neurons prevents the learning impairments typically caused by sleep deprivation. Notably, Notch signaling itself does not appear to alter dopamine levels in the brain. Together, these findings indicate that canonical Notch signaling in a specific subset of glial cells is essential for short-term memory formation and is modulated by dopaminergic signaling. This suggests that sleep loss–induced disruption of dopaminergic transmission impairs learning by downregulating canonical Notch signaling. Since Notch homologs are highly expressed in mammalian glia, this pathway may be conserved and functionally relevant in other species, including humans.