Pharmacological rescue of isolation-induced socialand neurochemical deficits in Drosophila melanogaster

Social isolation (ISO) is a major risk factor for mood disorders, reflected in disrupted neurochemistry and social behavior. Totest whether five days of ISO induce a depression-like state in Drosophila melanogaster, we measured brain monoaminesand social interaction networks (SINs), focusing on dopamine (DA) and octopamine (OA), key regulators of motivation andreward. ISO reduced DA, OA, and tyramine (TA) while increasing acetylcholine, and produced disorganized SINs marked byweaker, shorter interactions, reduced clustering and centrality, and hyperactive, uncoordinated locomotion. To test for rescue,flies were fed L-DA, OA, or both during ISO. All treatments improved monoamine levels, with the combined supplementationnormalizing or exceeding DA and OA and reducing acetylcholine to control levels. A condition-specific social interactionnetworks (SINs) metrics enabled consistent, quantitative comparisons across groups. SIN analyses showed that L-DA or OAalone partially restored connectivity among individuals, whereas combined supplementation most effectively rescued networkcohesion, clustering, and centrality, approaching or exceeding group-housed controls. Null-model comparisons confirmed thatthe restored networks reflected genuine, non-random structure rather than chance co-movement. Our findings show that fivedays of ISO induce neurochemical and behavioral changes in D. melanogaster that resemble depression, and that combinedDA+OA supplementation robustly restores monoaminergic balance and complex social organization. These results suggest amechanistic link between brain monoamines and group-level social behavior, highlighting the neurochemical basis of socialdeficits and their pharmacological rescue.