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Noradrenergic activation of the basolateral amygdala facilitates memory specificity for similar events experienced close in time

Nature Neuroscience volume 28, pages 1910–1918 (2025)Cite this article

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Abstract

Noradrenergic activation of the basolateral amygdala (BLA) promotes strong and lasting memories of emotionally arousing experiences. However, in our lives, we often encounter similar events that may be confused and result in emotional strengthening of incorrect associations. Here we provide evidence, in rats, that noradrenergic activation of the BLA promotes the formation of discrete memories of similar events that were experienced close in time, via a miR-134-regulated consolidation process within the dentate gyrus of the hippocampus. Targeted downregulation of miR-134 in the hippocampus was sufficient to induce memory specificity, without affecting the strength of the memory. Notably, noradrenergic activation of the BLA did not recruit this hippocampal miR-134-mediated mechanism in enhancing memory of a single event. These findings indicate that the BLA engages a qualitatively different neural mechanism on an ‘as-needed’ basis to facilitate the separation of similar memory representations, enabling the selective strengthening of correct associations into long-term memory.

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Fig. 1: Posttraining NE in the BLA induces memory specificity.
Fig. 2: Posttraining NE in the BLA downregulates miR-134 within the dDG.
Fig. 3: Hippocampal miR-134 selectively affects memory specificity.
Fig. 4: NE in the BLA naturally engages this miR-134 mechanism.
Fig. 5: NE in the BLA does not affect miR-134 after a single event.

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Data availability

Data are available via Zenodo at https://doi.org/10.5281/zenodo.15496898 (ref. 71) or in this paper and Supplementary Information.

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Acknowledgements

Funding was provided by Radboud University Topfund (to B.R.); Dutch Research Council Open Research Area grant (no. 464.18.110 to B.R.), and European Community’s Seventh Framework Programme (no. FP7/2007–2013) and Horizon 2020 Programme under grant agreement nos. 603016 and 667302 (to J.C.G.).

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Author notes

  1. These authors contributed equally: Mariana Pais, Giacomo Ronzoni, Chantal Schoenmaker, Piray Atsak.

Authors and Affiliations

  1. Department of Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands

    Erika Atucha, Mariana Pais, Giacomo Ronzoni, Chantal Schoenmaker, Piray Atsak, David Roura, Klara J. Lohkamp, Jeffrey C. Glennon & Benno Roozendaal

  2. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands

    Erika Atucha, Mariana Pais, Giacomo Ronzoni, Chantal Schoenmaker, Piray Atsak, David Roura, Klara J. Lohkamp, Jeffrey C. Glennon & Benno Roozendaal

  3. Functional Architecture of Memory Department, Leibniz Institute for Neurobiology, Magdeburg, Germany

    Erika Atucha

  4. Department of Psychobiology, School of Psychology, National University of Distance Learning (UNED), Madrid, Spain

    David Roura

  5. Department of Anesthesiology, University Hospital, Ludwig-Maximilians University, Munich, Germany

    Gustav Schelling

  6. Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA, USA

    James L. McGaugh

  7. Conway Institute for Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Belfield, Ireland

    Jeffrey C. Glennon

  8. Center for Scientific Review, National Institutes of Health, Bethesda, MD, USA

    Armaz Aschrafi

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Contributions

Conceptualization: E.A. and B.R. Data acquisition: E.A., M.P., G.R., C.S., P.A., D.R., K.L., G.S. and B.R. Funding acquisition: J.C.G. and B.R. Supervision: J.C.G., A.A. and B.R. Writing—original draft: E.A. and B.R. Writing—review and editing: J.L.M., J.C.G. and A.A. J.C.G. and A.A. contributed equally.

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Correspondence to Erika Atucha or Benno Roozendaal.

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Extended data

Extended Data Fig. 1 NE administration into the BLA of home-cage control rats does not affect miR-134, CREB or BDNF levels within the dDG.

NE (1.0 µg in 0.2 µl) was administered unilaterally into one BLA and saline into the other BLA, counterbalanced across animals, of home-cage control rats. NE administration did not affect miR-134, CREB or BDNF levels within the dDG 30 min later. mRNA levels are normalized to the saline-treated hemisphere (mean + s.e.m.) (n = 9, paired Student’s t-test: miR-134: t8 = 0.52, P = 0.62; CREB: t8 = 0.46, P = 0.66; BDNF: t8 = 0.98, P = 0.36).

Extended Data Fig. 2 Ant-134 administration into the dHPC does not alter Arc, Npas4 or c-Fos levels within the dDG.

Ant-134 (10 pmol in 0.5 µl) was administered unilaterally into one dHPC and scrambled control (Scr, 10 pmol in 0.5 µl) into the other dHPC, counterbalanced across animals, immediately after training on the dual-event inhibitory avoidance task. Ant-134 administration did not affect mRNA levels of several plasticity-related genes that are considered non-targets of miR-134 within the dDG 30 min later. mRNA levels are normalized to the scrambled-treated hemisphere (mean + s.e.m.) (n = 7, paired Student’s t-test: activity-regulated cytoskeleton-associated protein (Arc): t6 = 1.73, P = 0.13; neuronal PAS domain protein 4 (Npas4): t6 = 1.86, P = 0.11; c-Fos: t6 = 1.09, P = 0.32).

Extended Data Fig. 3 Noradrenergic activation of the BLA does not increase CREB or pCREB protein levels within the ventral blade of the DG.

NE (1.0 µg in 0.2 µl) was administered unilaterally into one BLA and saline into the other BLA, counterbalanced across animals, immediately after training on the dual-event inhibitory avoidance task. NE administration did not affect CREB or pCREB protein levels within the ventral blade of the DG granule cell layer 3 h later. Protein levels are normalized to the saline-treated hemisphere (mean + s.e.m.) (n = 7, paired Student’s t-test: CREB: t6 = 1.43, P = 0.20; pCREB: t6 = 1.01, P = 0.35).

Extended Data Fig. 4 Overexpression of miR-134 in the dHPC induces an efficient down-regulation of CREB and BDNF mRNA levels within the dDG.

Mimic-134 (0.25 pmol in 0.5 µl) was administered unilaterally into one dHPC and non-target control (NT, 0.25 pmol in 0.5 µl) into the other dHPC, counterbalanced across animals, immediately after training on the dual-event inhibitory avoidance task. Mimic-134 administration resulted in a 6.60 ± 0.91 log2FC (mean ± s.e.m) increase in total-tissue miR-134 levels within the dDG 30 min later (n = 6, paired Student’s t-test: t5 = 7.26, P < 0.01). mRNA levels are normalized to the non-target-treated hemisphere (mean + s.e.m.) (n = 6, paired Student’s t-test: CREB: t5 = 3.22, P < 0.05; BDNF: t5 = 3.28, P < 0.05). *P < 0.05 vs non-target.

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Atucha, E., Pais, M., Ronzoni, G. et al. Noradrenergic activation of the basolateral amygdala facilitates memory specificity for similar events experienced close in time. Nat Neurosci 28, 1910–1918 (2025). https://doi.org/10.1038/s41593-025-02014-0

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