Drosophila Exercise‐Training Requires Octopaminergic Neuron Activity

Endurance exercise is a promising therapeutic intervention with substantial protective effects on multiple indices of healthspan, including muscle and cardiac function. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies induce negative geotaxis but fail to sustain strong behavioral response during the training period. As a result, females do not experience the adaptive training response seen in males. Here, we demonstrate that poor female exercise response is mediated by differences in neuronal activity, not by differences in muscle. We also show that the sex‐specific exercise‐training response is reversible even in adults, after development has been completed. Using tissue‐autonomous expression of sex determination constructs, we have identified octopaminergic neurons as sufficient to govern adult exercise behavior. Importantly, manipulating octopaminergic neurons is also sufficient to induce conserved cellular and physiological changes seen following endurance training. Reversal of sex‐specific response can also be accomplished by providing octopamine or octopamine antagonist in food. Octopamine, the invertebrate ortholog of norepinephrine, is an important neuropeptide involved in diverse behaviors as well as learning, memory and reward. This model provides an important opportunity to further examine the specific pathways mediating reward‐based behavioral and physiological changes.