A voltage-dependent switch underlies efficient yet specific learning and memory.

Learning is vital for animal survival, but it must balance two conflicting demands: sensitivity (to avoid false negatives) and specificity (to avoid false positives). Improving one often worsens the other. Using Drosophila olfactory learning, we unravel how animals successfully perform both tasks. In Drosophila, odors are sparsely represented by cholinergic Kenyon cells (KCs). KCs form lateral axonal connections mediated by the muscarinic type-B receptor (mAChR-B), which suppresses non-specific learning. Using functional imaging, behavior, electrophysiology, and mathematical modeling, we show that mAChR-B is voltage dependent, switching between high- and low-activity states. In its high-activity state, it blocks plasticity in inactive KCs, whereas in its low-activity state, it permits plasticity in active KCs. This voltage-dependent switch enables differential neuromodulation, allowing learning to be both efficient and specific, minimizing both error types. Our findings reveal a novel mechanism for precise neuromodulatory control, reshaping our understanding of neuronal communication.