Fasting Rescues Locomotion in Neuromodulation-Deficient C. elegans via Octopamine-Gαq Signaling

Nutrient deprivation induces adaptive behavioral and physiological changes that are critical for survival. Here, we demonstrate that fasting ameliorates locomotion defects in Caenorhabditis elegans mutants lacking UNC-31/CAPS, a protein essential for dense-core vesicle (DCV)-mediated neuromodulation. Through forward genetic screening, we identified a gain-of-function mutation in egl-30, which encodes the heterotrimeric G protein subunit Gq, that suppresses the locomotion defects of unc-31 mutants under fed conditions. Transcriptomic analyses revealed that fasting induces upregulation of egl-30 and its downstream effectors in unc-31 mutants. Remarkably, exogenous octopamine treatment, which activates EGL-30/Gq signaling, mimicked the fasting response and restored locomotion in an EGL-30-dependent manner. Our findings uncover a mechanism of neuromodulatory plasticity, in which metabolic stress activates a compensatory octopamine-Gq signaling cascade to bypass impaired DCV-mediated neuromodulation, and suggest potential therapeutic strategies for CAPS-related neuropsychiatric disorders.