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Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice

Neuropsychopharmacology (2024)Cite this article

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Abstract

Methamphetamine, a commonly abused drug, is known for its high relapse rate. The persistence of addictive memories associated with methamphetamine poses a significant challenge in preventing relapse. Memory retrieval and subsequent reconsolidation provide an opportunity to disrupt addictive memories. However, the key node in the brain network involved in methamphetamine-associated memory retrieval has not been clearly defined. In this study, using the conditioned place preference in male mice, whole brain c-FOS mapping and functional connectivity analysis, together with chemogenetic manipulations of neural circuits, we identified the medial prefrontal cortex (mPFC) as a critical hub that integrates inputs from the retrosplenial cortex and the ventral tegmental area to support both the expression and reconsolidation of methamphetamine-associated memory during its retrieval. Surprisingly, with further cell-type specific analysis and manipulation, we also observed that methamphetamine-associated memory retrieval activated inhibitory neurons in the mPFC to facilitate memory reconsolidation, while suppressing excitatory neurons to aid memory expression. These findings provide novel insights into the neural circuits and cellular mechanisms involved in the retrieval process of addictive memories. They suggest that targeting the balance between excitation and inhibition in the mPFC during memory retrieval could be a promising treatment strategy to prevent relapse in methamphetamine addiction.

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Fig. 1: Characteristics of changes in the activity of brain regions and their functional network during the retrieval of methamphetamine (METH)-associated conditioned place preference (CPP) memory.
Fig. 2: Inhibition of the medial prefrontal cortex (mPFC) suppressed both recent and remote METH-associated CPP memory expression and reconsolidation.
Fig. 3: Differential roles of mPFC projecting neurons in the retrosplenial cortex (RSC) and ventral tegmental area (VTA) during METH-associated CPP memory retrieval.
Fig. 4: mPFC excitatory and inhibitory neurons differentially regulate METH-associated CPP memory expression and reconsolidation.
Fig. 5: METH-associated CPP memory retrieval induces transcriptional changes in the mPFC.

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Data availability

The RNA sequencing data generated for this study can be found in the GEO repository under accession number GSE249153. Further information of this study is available upon reasonable request from the corresponding authors, Hu Zhao (zhaohu3@mail.sysu.edu.cn) and Xiaojing Ye (yexiaoj8@mail.sysu.edu.cn).

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Acknowledgements

We thank the animal facility and the core facility of the Zhongshan School of Medicine, Sun Yat-sen University. We thank Dr. Wei-Jye Lin for the helpful discussions. We also thank all members of the Zhao lab, Ye lab and Lin lab for valuable and helpful discussions and technical assistance during this project.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81871535, No. 32271068), Key Project of the Basic and Applied Basic Research Foundation & Regional Joint Foundation of Guangdong Province, China (2021B1515120020), and the Science and Technology Planning Project of Guangdong Province, China (No. 2023B1212060018).

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  1. Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Yu-Bo Hu, Xi Deng, Lu Liu, Can-Can Cao, Ya-Wen Su, Zhen-Jie Gao, Xin Cheng, Deshan Kong, Qi Li, Yan-Wei Shi, Xiao-Guang Wang, Xiaojing Ye & Hu Zhao

  2. Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Yu-Bo Hu, Yan-Wei Shi, Xiao-Guang Wang, Xiaojing Ye & Hu Zhao

  3. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Yu-Bo Hu, Yan-Wei Shi, Xiao-Guang Wang, Xiaojing Ye & Hu Zhao

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Contributions

HZ, XY and X-GW conceptualized and designed the research project; Y-BH and XD performed majority of the experiments. LL, C-CC, Z-JG, XC, DK, Y-WS and QL helped analyze the data. Y-BH, HZ, XY and X-GW wrote the manuscript.

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Correspondence to Xiaojing Ye or Hu Zhao.

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Hu, YB., Deng, X., Liu, L. et al. Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01879-2

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