dArc1 controls sugar reward valuation in Drosophila melanogaster.

The Arc genes-which include Drosophila Arc1 and Arc2 (dArc)-evolved from Ty3 retrotransposons and encode proteins that form virus-like capsids. These capsids enable a novel form of intercellular communication by transferring RNAs between cells. However, the specific neuronal circuits and brain processes controlled by Arc signaling remain unidentified. Here, we show that loss of both dArc genes in Drosophila melanogaster enhances associative learning in an appetitive conditioning paradigm, where flies associate an odor with sugar rewards. This increased learning performance arises from an increased valuation of sugar rewards: unlike wild-type flies, dArc(-/-) flies form abnormally strong associations even when the sugar reward is small or has no caloric value. We found that the γ5-dopaminergic neurons of the protocerebral anterior medial (PAM) cluster, which encode the positive valence of sugar rewards, show heightened activity in response to sucrose in dArc(-/-) flies. We further show that the learning phenotype of dArc(-/-) flies depends on the formation of capsids, underscoring a direct role for capsid-mediated Arc signaling in sugar valuation. Our findings establish dArc genes as critical regulators of reward valuation in D. melanogaster, acting through a non-cell-autonomous mechanism that relies on capsid-mediated communication between cells.