Myelin plasticity in ventral tegmental area is required for opioid reward

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. One-Sentence Summary Activity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward ### Competing Interest Statement R.C.M. is on the scientific advisory boards of MapLight Therapeutics, MindMed, Cyclerion, AZ Therapies, Bright Minds Biosciences and Aelis Farma. M.M holds equity in MapLight Therapeutics and Syncopation Life Sciences.