Neuronal FICD shapes motivated behavior through modulation of dopamine receptor dynamics

Abstract

Motivated behaviors rely on dopaminergic signaling, which in turn depends on the correct folding and trafficking of receptors through the endoplasmic reticulum (ER). Within the ER, the AMPylase enzyme FICD acts as a molecular rheostat through its modification of the chaperone BiP, dynamically tuning the organelle’s responsiveness to folding perturbations and cellular stress. While the biochemistry of FICD is well-established, its role in complex animal behavior remains poorly understood. Here, we identify FICD as a conserved contributor to the generation of motivated behavior. In Drosophila, pan-neuronal knockdown of dFic significantly reduces feeding, spontaneous locomotion, and reward-seeking behavior. These alterations occur without disrupting circadian architecture, motor capacity, or homeostatic hunger, indicating a specific loss of motivational drive. Depleting dFic within subsets of dopamine receptor-expressing (Dop1R1) neurons recapitulates these behavioral alterations. Transcriptomic profiling reveals that dFic depletion does not induce a canonical unfolded protein response, pointing to a specific post-transcriptional alteration rather than global ER stress. At the molecular level, dysregulated dFic alters the localization and abundance of Dop1R1. Finally, we demonstrate that this regulatory axis is evolutionarily conserved, as loss of FICD similarly diminishes motivated behaviors in C. elegans and mice. Together, these findings implicate FICD in the generation of motivated behavior and link dynamic control of ER proteostasis to dopamine-receptor maturation. Significance Statement Loss of motivation is a disabling, poorly treated feature of depression, Parkinson’s disease, schizophrenia, addiction, and aging, and it is often attributed to alterations in dopaminergic pathways. Our work points to a distinct and underexplored mechanism of dysfunction: the capacity of neurons to fold and deliver dopamine receptors to their functional sites. By connecting a conserved enzymatic ER switch to motivated behavior across species, this study links cellular protein quality control to neuromodulation. It suggests that behavioral drive depends on how well neurons tune folding capacity to receptor demand. Because G-protein–coupled receptors are the largest class of drug targets, enhancing receptor maturation may offer new therapeutic avenues for motivational disorders.