Arc capsid signaling between serotonergic and dopaminergic neurons sets sleep depth in Drosophila

Arc genes evolved from Ty3 retrotransposons and encode proteins that self-assemble into virus-like capsids that package and transfer RNA between cells. This capsid-forming property may mediate a form of intercellular signaling distinct from classical synaptic transmission, but whether it operates within a defined neuronal system to control an ongoing behavior remains unclear. Here we show that Arc-dependent capsid signaling links serotonergic and PAM neurons to set sleep depth in Drosophila melanogaster. Loss of dArc genes deepened and consolidated sleep, increasing both sleep depth and the arousal threshold to mechanical stimulation, while leaving the diurnal sleep pattern intact. dArc1 was required in serotonergic neurons and, to a lesser extent, in PAM neurons, and both the loss-of-function phenotype and its rescue depended on capsid formation. Knocking down dArc1 in Sas-expressing cells, or Ptp10D in PAM neurons, reproduced the deeper, more consolidated sleep of dArc-/-flies, implicating the Sas-Ptp10D machinery in this signaling. These results identify Arc-dependent capsid signaling as a mechanism that links two modulatory neuronal populations to regulate an ongoing homeostatic behavior.