Gaitanidis, A., Pampanin, V., Thiem, J., Kalaras, G., Huthmacher, L., Hürkey, S., Kadas, D., Dimitriadou, A., Ntogka, A., Sanyal, S., Consoulas, C., Duch, C. (2025). The Drosophila escape motor circuit shows differential vulnerability to aging linked to functional decay.  PLoS Biol. 23(12): e3003553.

FBrf0264048

Research paper

Brain aging can cause cognitive and motor disabilities which often correlate with changes in dendritic branch, axon collateral, and synapse numbers. However, from invertebrates to mammals, age-related decline is typically restricted to specific neuron types or brain parts, indicating differential vulnerability. The rules to pinpoint the susceptibility of distinct brain elements to aging remain largely unknown. Here, we combine longitudinal studies with neuroanatomical, electrophysiological, and optophysiological analyses in the Drosophila genetic model to identify aging-susceptible and aging-resilient elements in a sensorimotor circuit that underlies escape. Young and mid-aged flies escape predator-like visual stimuli with a jump followed by flight, but behavioral performance declines with age. Mapping the underlying functional decline into the brain shows that most circuit components are robust against aging and remain functional even in old flies that have lost the behavior. By contrast, behavioral decline is caused by the selective decay of synaptic transmission between one specific visual projection neuron type (LC4) and the dendrite of one identified descending neuron (GF). Structurally, presynaptic active zone marker density is reduced whereas postsynaptic marker density remains normal. Other central synapses in this circuit as well as neuromuscular synapses are robust to aging. The synaptic connection susceptible to aging is also the circuit element most vulnerable to starvation or oxidative stress. Moreover, the vulnerable circuit element is also required for habituation, and thus, underlying circuit plasticity. In conjunction with data from mammalian brains our data suggest that a trade-off for functional neural circuit plasticity might be vulnerability to aging.