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Stress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories

Molecular Psychiatry volume 27, pages 3795–3805 (2022)Cite this article

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A Correction to this article was published on 09 June 2022

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Abstract

Generalization, the process of applying knowledge acquired in one context to other contexts, often drives the expression of similar behaviors in related situations. At the cellular level, generalization is thought to depend on the activity of overlapping neurons that represent shared features between contexts (general representations). Using contextual fear conditioning in mice, we demonstrate that generalization can also occur in response to stress and result from reactivation of specific, rather than general context representations. We found that generalization emerges during memory retrieval, along with stress-induced abnormalities of septohippocampal oscillatory activity and acetylcholine release, which are typically found in negative affective states. In hippocampal neurons that represent aversive memories and drive generalization, cholinergic septohippocampal afferents contributed to a unique reactivation pattern of cFos, Npas4, and repressor element-1 silencing transcription factor (REST). Together, these findings suggest that generalization can be triggered by perceptually dissimilar but valence-congruent memories of specific aversive experiences. Through promoting the reactivation of such memories and their interference with ongoing behavior, abnormal cholinergic signaling could underlie maladaptive cognitive and behavioral generalization linked to negative affective states.

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Fig. 1: SD triggers abnormalities of hippocampal cholinergic signaling contributing to SIG.
Fig. 2: SD triggers changes in MS oscillations and induces SIG through MS-DH projections.
Fig. 3: Optogenetic stimulation of MS-DH projections increases freezing in Context B.
Fig. 4: SD alters the reactivation of NRAM-GFP expressing neurons assessed by co-localization with cFos and Npas4.
Fig. 5: Chemogenetic inhibition of NRAM- but not FRAM-expressing neurons alleviates SIG.
Fig. 6: SD-induced reduction of REST levels in NRAM-GFP neurons was reversed by chemogenetic inhibition of MS-DH cholinergic projections.

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The data that support the findings of this study and the analysis code are available from the authors on reasonable request.

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Acknowledgements

We thank Gail Mandel (Oregon Health & Science University) for providing the REST antibody, Ryan Drenan (Wake Forest School of Medicine) for providing advice with behavioral analyses of Chat-Cre mice, John A. Kessler (Northwestern University) for helping us finalize the immunohistochemistry studies in his lab, and Gordon Shepherd (Northwestern University) for discussions and feedback on the circuit approaches.

Author contributions

LYR performed the behavioral, chemogenetic, and RAM experiments and data analysis and helped writing the manuscript. AC performed the optogenetic and fiber photometry experiments and analyzed the data, HZ performed the LFP experiments and data analyses, MAAM helped with the behavioral experiments and histochemical analyses, PG helped with the virus injection and expression analyses, ZP performed the circuit manipulations and RAM/REST studies, XS and YL provided all of the RAM constructs and shared key expertise in experimental design with RAM manipulations, JR designed the overall study, helped with data analysis, and wrote the manuscript.

Funding

This work was funded by NIMH grants MH078064 and MH108837 and Lundbeck Foundation grant R310-2018-3611 to JR, F30MH122130, and T32MH067564 to LR, and NS115543 to YL.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Northwestern University, Evanston, IL, USA

    Lynn Y. Ren, Ana Cicvaric, Hui Zhang, Mariah AA Meyer, Anita L. Guedea, Pan Gao & Jelena Radulovic

  2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Ana Cicvaric, Hui Zhang, Zorica Petrovic & Jelena Radulovic

  3. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    Xiaochen Sun & Yingxi Lin

  4. Department of Psychiatry, State University of New York Upstate Medical University, New York, NY, USA

    Yingxi Lin

  5. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY, USA

    Jelena Radulovic

  6. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Jelena Radulovic

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  1. Lynn Y. Ren
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Correspondence to Jelena Radulovic.

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All animal procedures used in this study were approved by the Northwestern University IACUC and Albert Einstein Medical College IACUC and complied with federal regulations set forth by the National Institutes of Health.

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The original online version of this article was revised: In this article the author name Mariah AA Meyer was incorrectly written as Mariah M. A. A. Meyer.

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Ren, L.Y., Cicvaric, A., Zhang, H. et al. Stress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories. Mol Psychiatry 27, 3795–3805 (2022). https://doi.org/10.1038/s41380-022-01610-x

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