2. Academic Validation
  3. Distinct role of claustrum and anterior cingulate cortex bidirectional circuits in methamphetamine taking and seeking

Distinct role of claustrum and anterior cingulate cortex bidirectional circuits in methamphetamine taking and seeking

  • Nat Commun. 2025 Jul 25;16(1):6871. doi: 10.1038/s41467-025-62188-w.
Manqing Wu 1,  Miaojun Lai 2,  Yiyin Zhou 2,  Yingjie Cheng 1,  Sai Shi 1,  Fangmin Wang 2,  Huizhen Liu 2,  Min Zhao 3 4 5,  Wenhua Zhou 6 7
Affiliations

Affiliations

  • 1 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Zhejiang Provincial Key Laboratory of Addiction Research, The affiliated Kangning Hospital of, Ningbo University, Ningbo, P.R. China.
  • 3 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. drminzhao@smhc.org.cn.
  • 4 Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China. drminzhao@smhc.org.cn.
  • 5 CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China. drminzhao@smhc.org.cn.
  • 6 Zhejiang Provincial Key Laboratory of Addiction Research, The affiliated Kangning Hospital of, Ningbo University, Ningbo, P.R. China. whzhou@vip.163.com.
  • 7 Department of Psychiatry, Ningbo Kangning Hospital of, Ningbo, P.R. China. whzhou@vip.163.com.
PMID: 40715089 DOI: 10.1038/s41467-025-62188-w
Abstract

Methamphetamine (METH) addiction involves escalating intake with strong cue reactivity, and high relapse risk, yet its neural mechanism remains unclear. Using c-Fos mapping and machine learning, we identified the claustrum (CLA), a subcortical region reciprocally connected with the anterior cingulate cortex (ACC), as key mediators of both METH taking and seeking in self-administering male rats. Chemogenetic inhibition of CLA suppressed both drug consumption and cue-induced reinstatement, while ACC inhibition selectively reduced drug-seeking. Circuit tracing and manipulation revealed that the CLA-ACC circuit supported drug-taking, whereas the ACC-CLA circuit was specifically recruited during drug-seeking. Activity-dependent labeling showed that ACC ensembles activated by cues overlapped with those engaged during prior drug use. These findings suggest that CLA drives METH reward through the ACC, while the ACC gains cue salience and feeds back to CLA, reinforcing relapse. Targeting this bidirectional CLA-ACC circuit may provide novel therapeutic strategies for treating METH addiction.

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