biostudies-literatureUnknown28(10)Zhang THarbin Institute of Technology<i>Drosophila melanogaster</i> relies on complex brain circuits and neuromodulation for experience-dependent sexual behavior, yet the role of neuropeptide signaling in behavioral refinement remains unclear. We investigate SIFamide (SIFa) and its receptor (SIFaR) in regulating male <i>Drosophila</i> sexual behavior. SIFaR is essential for these behaviors, particularly interval timing. Knockdown in fru-positive neurons impairs courtship index (CI) and mating duration (MD) but not copulation latency (CL). Critically, SIFaR in GABAergic mAL neurons (fru⁺, dsx^-) specifically controls MD and CI, not CL. Additionally, SIFa signaling in mAL neurons of experienced males increases presynaptic terminals, indicating context-dependent synaptic plasticity. These results reveal a coiScience113516https://www.ebi.ac.uk/biostudies/studies/S-EPMC12483593biostudies-literatureSIFamide-dependent synaptic plasticity in male-specific GABAergic neurons underlies experience-modulated mating behaviors.PMC12483593Wu ZKim WJZhang TMiao HSong YfalseSIFamide-dependent synaptic plasticity in male-specific GABAergic neurons underlies experience-modulated mating behaviors.<i>Drosophila melanogaster</i> relies on complex brain circuits and neuromodulation for experience-dependent sexual behavior, yet the role of neuropeptide signaling in behavioral refinement remains unclear. We investigate SIFamide (SIFa) and its receptor (SIFaR) in regulating male <i>Drosophila</i> sexual behavior. SIFaR is essential for these behaviors, particularly interval timing. Knockdown in fru-positive neurons impairs courtship index (CI) and mating duration (MD) but not copulation latency (CL). Critically, SIFaR in GABAergic mAL neurons (fru⁺, dsx^-) specifically controls MD and CI, not CL. Additionally, SIFa signaling in mAL neurons of experienced males increases presynaptic terminals, indicating context-dependent synaptic plasticity. These results reveal a co2025-01-01T00:00:00Z2025 Oct2026-07-15T06:03:47.105Z2026-06-30T03:20:16.962ZS-EPMC124835934103569110.1016/j.isci.2025.113516