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 α subunit Gαq, 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/Gαq 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-Gαq signaling cascade to bypass impaired DCV-mediated neuromodulation, and suggest potential therapeutic strategies for CAPS-related neuropsychiatric disorders.