Meshi Micheala¹, Levi Mali¹ & Shohat-Ophir Galit¹

Motivation is an internal representation of physiological needs that drives goal-directed behavior, ensuring that actions are expressed at the appropriate time, intensity, and context. Although the neurobiology of motivation has been extensively studied, the mechanisms by which motivational drives accumulate over time and are translated into sustained behavioral states remain poorly understood. Konrad Lorenz’s hydraulic model proposes that motivation builds gradually like pressure in a reservoir, yet the existence and nature of a corresponding biochemical mechanism remain unclear. In this study, we tested the hypothesis that drive buildup is encoded by the accumulation of prion-like proteins within neurons that function as motivational hubs. We focused on the Drosophila neuropeptide F (NPF) system, which is homologous to the mammalian NPY system, and examined the role of the prion-like RNA-binding protein Orb2, which undergoes state-dependent oligomerization and regulates local protein synthesis at synapses. Using microscale thermophoresis, western blotting, and confocal imaging, we quantified Orb2 monomeric and oligomeric states in vivo under distinct internal drives. The result demonstrate that prolonged starvation, but not acute water deprivation, induced increased Orb2 accumulation and a shift toward oligomerization in NPF neurons, with enrichment at synapses of a subset of neurons projecting to the fan-shaped body and suboesophageal zone. This accumulation was reversible upon refeeding. In contrast, neurons expressing the NPF receptor showed reduced Orb2 accumulation during food deprivation, consistent with reciprocal signaling. Functionally, Orb2 oligomerization was required for starvation-induced synaptic localization of neuropeptide F released from NPF neurons. Together, these findings support a model in which Orb2 acts as a reversible molecular integrator of metabolic state, linking internal energy deficit to sustained neuromodulatory remodeling in feeding-related circuits, and providing a framework for future work on graded drive and downstream RNA targets.

1 The Mina & Everard Goodman Faculty of Life Sciences, The Multidisciplinary Brain Research Center and, Institute
for Nanotechnology and Advanced Materials, Bar-Ilan University, Israel