Dadyala, T. S. | bioRxiv Science

bioRxiv2026

Cellular source and circuit context organize functional specificity in the Drosophila NPF system

Neuropeptides regulate diverse and sometimes opposing functions, yet how a single peptide achieves functional specificity remains unclear. Receptor diversity can provide specificity, but not in systems with only one receptor. Drosophila neuropeptide F (NPF) acts through a single receptor, providing a model to test whether specificity is organized by the peptide's cellular source. Using the whole-brain connectome, we defined four adult NPF cell types with no shared first-order synaptic partners and separate networks. These cell types made distinct and partly opposing contributions to reinforcement, feeding, mating, and energy storage. Most peptide-dependent effects were undetectable after population-level NPF reduction, showing that global perturbation can obscure source-specific functions. Changing neuronal activity and reducing NPF in the same cells produced different, sometimes opposing, phenotypes, so neuronal activation cannot be equated with peptide action. Thus, cellular source and circuit context generate functional specificity that population-level perturbation conceals.

neuroscience↗

bioRxiv2025

From perception to valence: a pair of interneurons that assign positive valence to sweet sensation in Drosophila

Assigning valence--appeal or aversion--to gustatory stimuli and relaying it to higher-order brain regions to guide flexible behaviors is crucial to survival. Yet the neural circuit that transforms gustatory input into motivationally relevant signals remains poorly defined in any model system. In Drosophila melanogaster, substantial progress has been made in mapping the sensorimotor pathway for feeding and the architecture of the dopaminergic reinforcement system. However, where and how valence is first assigned to a taste has long been a mystery. Here, we identified a pair of subesophageal zone interneurons in Drosophila, termed fox, that impart positive valence to sweet taste and convey this signal to the mushroom body, the flys associative learning center. We show that fox neuron activity is necessary and sufficient to drive appetitive behaviors and can override a tastants intrinsic valence without impairing taste quality discrimination. Furthermore, fox neurons transmit the positive valence to specific dopaminergic neurons that mediate appetitive memory formation. Our findings reveal a circuit mechanism that transforms sweet sensation into a reinforcing signal to support learned sugar responses. The fox neurons exhibit a convergent-divergent "hourglass" circuit motif, acting as a bottleneck for valence assignment and distributing motivational signals to higher-order centers. This architecture confers both robustness and flexibility in reward processing--an organizational principle that may generalize across species.

neuroscience↗