Contextualized phenovectors reveal a Drosophila serotonergic circuit controlling satiety

Distinguishing whether a neural circuit genuinely controls a holistic behavioral state, rather than merely producing isolated effects, is a central challenge in neuroscience. Feeding research illustrates the problem: decades of work have reached conflicting conclusions partly because individual behavioral features are assessed in isolation. Here we establish a contextualized ethomics approach that benchmarks optogenetic circuit manipulations against natural hunger-satiety transitions, using high-dimensional behavioral tracking in Drosophila and starvation as a ground-truth intervention. Applying this framework, we find that serotonergic neurons marked by the Tryptophan hydroxylase neuronal (Trhn) enhancer are both required for and instructive of a satiety-like state, whereas other feeding-related circuits produce only fragmentary behavioral changes. Intersectional dissection localized this control to Trhn neurons of the ventral nerve cord, which act through the sugar transporter Sut2 to sense nutrient state. This work strengthens our understanding of serotonergic feeding control and provides a generalizable framework for validating circuit-state relationships.