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Targeting Nociceptin/Orphanin FQ receptor to rescue cognitive symptoms in a mouse neuroendocrine model of chronic stress

Molecular Psychiatry (2023)Cite this article

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Abstract

Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.

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Fig. 1: Effect of NOP receptor antagonists on memory.
Fig. 2: Effect of NOP receptor antagonists on long-term recognition and location memory deficits in the chronic stress model.
Fig. 3: Lack of modulation of anxiety, depressive-like behavior, and HPA axis reactivity by the NOP antagonist in the chronic stress model.
Fig. 4: Modulation of N/OFQ precursor and NOP receptor mRNA expression by chronic CORT.
Fig. 5: Modulation of neuronal activity in the hippocampus following memory acquisition after chronic CORT and acute SB-612,111 treatment.
Fig. 6: Conditional knockout of NOP receptor in the hippocampus restores long-term recognition and location memory performances following chronic CORT exposure.

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Acknowledgements

We thank the CBI-Anexplo mouse facility. We also thank the LITC imaging platform of Toulouse TRI, and Sébastien Gauzin from the Mouse Behavioral Core of CBI-Anexplo for support. We thank Dr Catherine Mollereau for critical reading of the manuscript.

Funding

This work was supported by the Centre National de la Recherche Scientifique (to LM), the Research Center on Animal Cognition (to LM), the French Ministry of Research (to FD), NIH grants, R21DA034929, and P50MH119467 (to MB).

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Authors and Affiliations

  1. Research Center on Animal Cognition (CRCA), Center of Integrative Biology (CBI), University of Toulouse, CNRS UMR-5169, UPS, Toulouse, France

    Flora D’Oliveira da Silva, Cathaline Robert, Bruno P. Guiard & Lionel Moulédous

  2. IRBA (Army Biomedical Research Institute), Brétigny-sur-Orge, France

    Emma Lardant & Frédéric Chauveau

  3. Department of Anesthesiology; Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE), University of Washington, Seattle, WA, 98195, USA

    Carina Pizzano & Michael R. Bruchas

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  1. Flora D’Oliveira da Silva
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Contributions

Conceptualization: FD, BG, LM; Methodology: FD, FC, MB, LM; Resources: CP, MB; Formal analysis: FD, BG, LM; Investigation: FD, CR, EL, LM; Visualization: FD; Writing—Original Draft: FD, LM; Writing—Review & Editing: FD, MB, BG, FC, LM; Funding Acquisition: FD, MB, LM; Supervision: FC, LM.

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Correspondence to Lionel Moulédous.

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D’Oliveira da Silva, F., Robert, C., Lardant, E. et al. Targeting Nociceptin/Orphanin FQ receptor to rescue cognitive symptoms in a mouse neuroendocrine model of chronic stress. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02363-x

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