Reduced dopaminergic reinforcement, not learning capacity, limits operant learning in aging Drosophila

Authors

Jahan, I., Holvoet, H., De Backer, J.-F., Grunwald Kadow, I. C.

Abstract

Aging is associated with a progressive decline in cognitive function, including the ability to adapt behavior based on its consequences. While classical conditioning in Drosophila melanogaster has provided key insights into reinforcement learning, how aging impacts operant learning and adjusting behavior based on action outcomes remains unclear. Here, we used a closed-loop optogenetic paradigm to test how aging affects operant learning and the role of dopaminergic neurons (DANs; PPL1 and PAM) in this process. Activation of distinct DAN subsets revealed that both young and aged flies retain PPL1-dependent avoidance learning, indicating preserved action-outcome learning with age. However, learning in aged flies depended on prolonged reinforcement: unlike young flies, they failed to learn under shorter optogenetic stimulation durations, suggesting an aging-associated reduced dopaminergic reinforcement rather than a loss of learning capacity. Moreover, reducing mitochondrial antioxidant capacity via SOD2 knockdown in PPL1 neurons phenocopied the aging-related deficit, implicating oxidative stress in impaired reinforcement signaling. In contrast, broad PAM neuron activation drove robust learning across ages and stimulation regimes. Nevertheless, functional dissection of PAM subpopulations revealed subtype-specific aging-associated vulnerability within dopaminergic circuits. In line with the behavioral data, PPL1 but not PAM neurons exhibited age-dependent reductions in cell size. Together, our findings suggest that aging selectively reduces dopaminergic reinforcement in a DAN subtype-dependent manner while preserving the capacity for operant learning. Increasing reinforcement length rescues this deficit, indicating that altered dopaminergic signaling, rather than impaired learning capacity, is a key driver of age-related cognitive decline.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Jun 2026.

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