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

Acta Pharmacologica Sinica (2026)Cite this article

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 SCGlu+–VTADA+–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.

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Fig. 1: Silencing the SC→VTA pathway attenuates MA-taking behavior.
Fig. 2: Glutamatergic and DAergic neurons in the SC–VTA pathway are activated during visual cue-induced reinstatement.
Fig. 3: Manipulation of the SCGlu+–VTADA+ pathway significantly affected visual cue-induced reinstatement.
Fig. 4: SC–VTADA+–NAcore pathway is involved in visual cue-induced reinstatement.

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Data available on request from the authors.

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (2023YFC3304201).

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Author notes

  1. These authors contributed equally: Xing-fang Cun, Man-yi Jing, Meng-die Yang

Authors and Affiliations

  1. Academy of Military Medical Sciences, Beijing, 100850, China

    Xing-fang Cun, Man-yi Jing, Meng-die Yang, Ning Wu, Jin Li & Rui Song

  2. State Key Laboratory of National Security Specially Needed Medicines, Beijing, 100039, China

    Xing-fang Cun, Man-yi Jing, Meng-die Yang, Ning Wu, Jin Li & Rui Song

  3. Department of Pharmacy, The Medical Support Center of PLA General Hospital, Beijing, 100853, China

    Man-yi Jing

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  1. Xing-fang Cun
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Contributions

XFC: investigation, methodology, data curation. MYJ: writing—original draft, validation. MDY: visualization, methodology, data curation. NW: writing—review and editing, investigation, conceptualization. JL: writing—review and editing, supervision, investigation, conceptualization. RS: writing—review and editing, supervision, investigation, funding acquisition, conceptualization.

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Correspondence to Jin Li or Rui Song.

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Cun, Xf., Jing, My., Yang, Md. et al. A novel superior colliculus circuit mediates visual cue-driven methamphetamine taking and seeking. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01733-1

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