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A disinhibitory microcircuit of the orbitofrontal cortex mediates cocaine preference in mice

Molecular Psychiatry (2024)Cite this article

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Abstract

Both clinical and animal studies showed that the impaired functions of the orbitofrontal cortex (OFC) underlie the compulsive drug-seeking behavior of drug addiction. However, the functional changes of the microcircuit in the OFC and the underlying molecular mechanisms in drug addiction remain elusive, and little is known for whether microcircuits in the OFC contributed to drug addiction-related behaviors. Utilizing the cocaine-induced conditioned-place preference model, we found that the malfunction of the microcircuit led to disinhibition in the OFC after cocaine withdrawal. We further showed that enhanced Somatostatin-Parvalbumin (SST-PV) inhibitory synapse strength changed microcircuit function, and SST and PV inhibitory neurons showed opposite contributions to the drug addiction-related behavior of mice. Brevican of the perineuronal nets of PV neurons regulated SST-PV synapse strength, and the knockdown of Brevican alleviated cocaine preference. These results reveal a novel molecular mechanism of the regulation of microcircuit function and a novel circuit mechanism of the OFC in gating cocaine preference.

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Fig. 1: Withdrawal from cocaine compromised inhibitory transmission in the OFC with different contributions from the OFC interneurons.
Fig. 2: Cocaine mice showed impaired function of the inhibitory microcircuit in the OFC.
Fig. 3: PV+ neurons of Cocaine mice received more inhibitory inputs from SST+ neurons.
Fig. 4: PV+ neurons of Cocaine mice showed increased ratio of SST + vGAT puncta density and perineuronal nets expression.
Fig. 5: Knockdown of Brevican of PNNs diminished place preference of Cocaine mice in CPP test.

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All data are available upon request.

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Acknowledgements

The research was supported in part by the Ministry of Science and Technology of China (STI2030-Major Projects 2021ZD0202900 and 2019YFA0706201, W.Z.), National Natural Science Foundation of China (32170960, W.Z.).

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  1. These authors contributed equally: Ziran Huang, Xiaoyan Wei, Jing Tian, Yangxue Fu.

Authors and Affiliations

  1. National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing, 100191, China

    Ziran Huang, Xiaoyan Wei, Jing Tian, Yangxue Fu, Jihui Dong, Yihui Wang, Jie Shi & Wen Zhang

  2. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital); Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100191, China

    Lin Lu

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Contributions

W.Z. conceived and designed the experiments. Z.H., X.W., J.T., Y.W, Y.F, J.D., and W.Z. performed the experiments. Z.H., J.T., Y.F. and W.Z. analyzed and interpreted the data. W.Z. wrote the manuscript.

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Correspondence to Wen Zhang.

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Huang, Z., Wei, X., Tian, J. et al. A disinhibitory microcircuit of the orbitofrontal cortex mediates cocaine preference in mice. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02579-5

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