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Elevated dorsal medial prefrontal cortex to lateral habenula pathway activity mediates chronic stress-induced depressive and anxiety-like behaviors

Neuropsychopharmacology (2024)Cite this article

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Abstract

The medial prefrontal cortex (mPFC) sends projections to numerous brain regions and is believed to play a significant role in depression and anxiety. One of the key downstream targets of the mPFC, the lateral habenula (LHb), is essential for chronic stress (CS)-induced depressive and anxiety-like behaviors. Nevertheless, whether the mPFC-LHb pathway mediates the co-occurrence of depression and anxiety and the underlying mechanism remain incompletely understood. Here, using chemogenetics, we first determined that activation of LHb-projecting mPFC neurons is essential for the development of depressive and anxiety-like behaviors induced by CS. Subsequently, we identify the extent and distribution of LHb-projecting neurons originating from the mPFC subregion. Through circuit-specific in vivo fiber photometry, we found that Ca2+ activity in dorsal mPFC (dmPFC) axon terminals within the LHb was increased during exposure to stressful and anxiety-related stimuli, highlighting the potential role of LHb-projecting dmPFC neurons in conveying stressful and anxiety-related information to the LHb. Finally, we observed that activation of both LHb-projecting dmPFC neurons and their postsynaptic counterparts in the LHb was necessary for CS-induced depressive and anxiety-like behaviors. Overall, this study provides multiple lines of evidence demonstrating that activation of the dmPFC-LHb pathway is a crucial neural circuitry for CS-induced depressive and anxiety-like behaviors.

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Fig. 1: Activation of LHb-projecting mPFC neurons is necessary for CS-induced depressive and anxiety-like behaviors.
Fig. 2: Extent and distribution of LHb-projecting neurons in mPFC subregions.
Fig. 3: Stressful and anxiety-related stimuli more strongly activated the dmPFC-LHb synapse among the mPFC subregions projecting to the LHb.
Fig. 4: Activation of LHb-projecting dmPFC neurons is necessary for CS-induced depressive and anxiety-like behaviors.
Fig. 5: Activation of LHb postsynaptic neurons projecting from the dmPFC is necessary for CS-induced depressive and anxiety-like behaviors.

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Data availability

The raw data that support the findings of the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Drs. Chaoran Ren and Jichun Zhang for their technical support.

Funding

This work was supported by the Science and Technology Program of Guangzhou (202201010195 for SL), the Guangdong Basic and Applied Basic Research Foundation (2023A1515010478 for SL; 2021B1515020035 for LH), National Natural Science Foundation of China (32171009 for LH), and Young Elite Scientist Sponsorship Program by CAST (YESS20210181 for LH).

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Authors and Affiliations

  1. Physiology Department, School of Medicine, Jinan University, Guangzhou, 510632, China

    Xiaohan Tong, Jijin Wu, Ruizhe Sun, Yingxi Hong, Ying Sun, Chunxiao Chen & Song Lin

  2. Guangdong-Hongkong-Macau CNS Regeneration Institute, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, 510632, China

    Han Li, Xianwei Liu, Lu Huang & Song Lin

  3. Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Lu Huang

  4. Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China

    Song Lin

  5. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Ministry of Education, Jinan University, Guangzhou, 510632, China

    Song Lin

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Contributions

SL and LH designed the experiments and wrote the manuscript. XHT, RZS, and YXH performed the behavioral experiments and in vivo fiber photometry experiments. XHT performed the surgery with the help of XWL and YS. JJW performed the electrophysiological recordings. XHT, RZS, HL, YS, and CXC performed histology and microscopy. XHT, JJW, YXH, LH, and SL analyzed the data.

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Correspondence to Lu Huang or Song Lin.

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Tong, X., Wu, J., Sun, R. et al. Elevated dorsal medial prefrontal cortex to lateral habenula pathway activity mediates chronic stress-induced depressive and anxiety-like behaviors. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01840-3

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