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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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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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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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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DOI: https://doi.org/10.1038/s41380-024-02579-5