TRPV1-Independent and Sex-Specific Capsaicin Signatures in Drosophila

In mammals, capsaicin activates the transient receptor potential vanilloid 1 (TRPV1) channel to induce pungency, but its effects in species lacking TRPV1 remain unclear. In Drosophila melanogaster, which has no TRPV1 ortholog, capsaicin triggers proboscis reflexes, drives attraction, and shapes feeding and locomotion in a sex- specific manner. Females exhibit delayed habituation and increased sleep fragmentation, whereas both sexes reduce evening locomotion. Single-nucleus RNA sequencing (snRNA-seq) revealed broader transcriptional responses in females, including modulation of peptidergic neurons and circadian-linked glial clusters. Cell–cell communication analyses identified a female-biased TGF-ß and AstA signaling axis in learning and memory centers, contrasting with male-enriched WNT, NPF, and Dh31 pathways. These results uncover TRPV1-independent mechanisms through which capsaicin influences neural circuits, highlighting sex-specific strategies for integrating sensory cues and providing a framework to explore the ecological and evolutionary significance of capsaicin sensitivity beyond nociception. Overall design: We collected brain samples from flies exposed to control and capsaicin diets to perform snRNA-seq. Female and male flies were collected during ZT6–12.