Serotonergic Modulation of Aggression in Drosophila Involves GABAergic and Cholinergic Opposing Pathways

Pathological aggression is commonly associated with psychiatric and neurological disorders and can impose a substantial burden and cost on human society. Serotonin (5HT) has long been implicated in the regulation of aggression in a wide variety of animal species. In Drosophila, a small group of serotonergic neurons selectively modulates the escalation of aggression. Here, we identified downstream targets of serotonergic input—two types of neurons with opposing roles in aggression control. The dendritic fields of both neurons converge on a single optic glomerulus LC12, suggesting a key pathway linking visual input to the aggression circuitry. The first type is an inhibitory GABAergic neuron: its activation leads to a decrease in aggression. The second neuron type is excitatory: its silencing reduces and its activation increases aggression. RNA sequencing (RNA-seq) profiling of this neuron type identified that it uses acetylcholine as a neurotransmitter and likely expresses 5HT1A, short neuropeptide F receptor (sNPFR), and the resistant to dieldrin (RDL) category of GABA receptors. Knockdown of RDL receptors in these neurons increases aggression, suggesting the possibility of a direct crosstalk between the inhibitory GABAergic and the excitatory cholinergic neurons. Our data show further that neurons utilizing serotonin, GABA, ACh, and short neuropeptide F interact in the LC12 optic glomerulus. Parallel cholinergic and GABAergic pathways descending from this sensory integration area may be key elements in fine-tuning the regulation of aggression. •Fly 5HT-producing neurons enhance aggression via two types of downstream target neurons•The downstream GABA neurons lower and ACh neurons promote aggression on activation•Both express 5HT1A receptors and collect input from the LC12 optic glomerulus•ACh neurons also express RDL-GABA receptors, suggesting a complex switch-like circuit Alekseyenko et al. report two types of neurons downstream of the 5HT aggression-modulating neurons in Drosophila, with opposite effects on the behavior. Both neurons express 5HT1A receptors, collect visual input from the same optic glomerulus, and form parallel crosstalking cholinergic and GABAergic pathways that fine-tune aggression display.