A novel superior colliculus circuit mediates visual cue-driven methamphetamine taking and seeking

Abstract

Addictive substances transform environmental cues into potent conditioned cues through reward-based associative learning. While visual cues are known to amplify drug-seeking behavior and trigger relapse, the neural circuits mediating their motivational salience remain incompletely understood. Here, we identified the superior colliculus (SC) as a critical encoder of drug-related visual information via gating reinstatement through a defined SC-VTA-NAcore pathway. We established a methamphetamine (MA) self-administration model in mice with fiber photometry, optogenetic, and chemogenetic techniques. Using fiber photometry, we discovered that the monosynaptic SC-VTA pathway exhibited selective activation during exposure to drug-paired visual cues, which demonstrated a stable cue encoding. Optogenetic inhibition of SC-VTA projections completely abolished cue-induced reinstatement, while activation potentiated reinstatement. Transsynaptic tracing confirmed a SC^Glu+-VTA^DA+-NAcore circuit. Bidirectional manipulation of this pathway demonstrated its necessity and sufficiency for controlling cue-triggered reinstatement. Our results establish the SC as a sensory-motivational hub that transforms visual drug cues into relapse-promoting signals through a hardwired midbrain circuit. The discovery of this SC-VTA-NAcore pathway provides both a mechanistic framework for understanding cue-driven addiction and concrete targets for interventions.

Keywords: methamphetamine addiction; nucleus accumbens core; relapse; superior colliculus; ventral tegmental area; visual cues.