Four neurons pattern brain-wide developmental activity through neuropeptide signaling.

In both vertebrates and invertebrates, the developing brain becomes electrically active before it is ready to process sensory input(1-4). During neural circuit maturation, developmental activity is thought to refine synaptic connections by driving neuronal co-activation in rhythmic patterns(5). Here we describe cellular interactions that shape brainwide developmental activity and their molecular basis. In Drosophila, patterned stimulus independent neural activity (PSINA) engages the entire brain in highly stereotyped, globally coordinated cycles of activity(6). A molecularly-defined population of ~2,000 neurons (Transient Receptor Potential Gamma, Trpγ+ neurons) act as an activity template for PSINA. We show that this activity template is patterned by four neurons expressing the neuropeptide SIFamide (SIFa)(7). Signaling through the SIFa Receptor(8), SIFa modulates the activity of both SIFa and Trpγ+ neurons to establish the brainwide activity cycles of PSINA. In turn, Trpγ+ neurons sustain SIFa neuron activity through a recurrent interaction. Neuropeptides modulate neuronal activity through synapse-free, or wireless, signaling(9); a fitting mode of communication for a process tasked with refining on-going synapse formation. By placing neuropeptide signaling at the core of developmental activity, this work highlights the rich neurophysiological potential of the chemical connectome in shaping the developing brain.