RESTORING TYRAMINE 1 RECEPTOR EXPRESSION REVERSES AGE-RELATED DEFICITS IN OCTOPAMINERGIC CALCIUM SIGNALING AND LOCOMOTION

During aging, nervous system function declines, resulting in cognitive and motor impairments that may be associated with dysfunction of the noradrenergic system, which regulates brain metabolism and behavior through adrenoceptor signaling. In astrocytes, this signaling facilitates glucose uptake, glycogen breakdown, and aerobic glycolysis, producing lactate that fuels neuronal activity. How aging disrupts this regulation remains unclear.
To investigate this, we expressed fluorescent Ca²⁺, cAMP, glucose, and lactate sensors in neurons or glia in the Drosophila brain and monitored changes in cytosolic second messengers and metabolites upon stimulation with octopamine, the invertebrate analogue of noradrenaline, during aging. Aged Drosophila exhibited neurodegeneration, reduced locomotion, and altered whole-brain metabolism. Aging reduced neuronal, but not astrocytic, capacity for extracellular glucose uptake, while lactate uptake was unaffected. Octopamine-induced increases in cytosolic lactate and glucose were diminished in astrocytes, whereas neurons exhibited prominent lactate increases that were preserved with age. While neuron-specific octopamine-induced cAMP signaling was not affected by aging, Ca²⁺ transients in both neurons and glia were nearly abolished in aged brains, indicating age-related impairment of Ca²⁺ signaling. This deficit is likely linked to downregulation of tyramine 1 receptors (Tyr₁Rs), as overexpression of Tyr₁Rs in octopaminergic Tdc2 neurons restored both Ca²⁺ signaling and locomotor performance.
Together, these findings reveal cell type–specific alterations in octopaminergic regulation of brain metabolism during aging and identify Tyr₁R-dependent Ca²⁺ signaling as a key contributor to motor function decline. The results highlight new targets for mitigating age-related noradrenergic dysfunction during neurodegeneration.