A superior colliculus-originating circuit prevents cocaine reinstatement via VR-based eye movement desensitization...

While Virtual Reality (VR) technology shows promise in the management of substance use disorders, the development of an effective VR-based extinction procedure remains lacking. In this study, we developed a VR-based eye movement desensitization and reprocessing extinction training program tailored for mice. We found that this VR treatment during cocaine extinction prevents reinstatement by suppressing the hyperactivation of glutamatergic excitatory neurons in the intermediate layers of the superior colliculus (SCi^CaMKIIα) during exposure to environmental cues. Additionally, SCi^CaMKIIα neurons innervate tyrosine hydroxylase-positive neurons in the locus coeruleus (LC^TH). Environmental cues trigger stronger phasic activation of LC^TH neurons through this SCi^CaMKIIα→LC^TH projection, leading to increased dopamine release onto the dorsal CA3 (dCA3) region, thereby facilitating reinstatement. Furthermore, we demonstrate that VR treatment effectively inhibits the neural circuitry involving SCi^CaMKIIα→LC^TH→dCA3 in response to environmental cues, thus preventing cocaine reinstatement. Our findings suggest that VR treatment may represent a promising strategy for achieving drug abstinence.