Abstract
The mammalian brain organises knowledge about entities in the world and relationships between them using cognitive maps. When forming a cognitive map, there is a necessary trade-off between extending the map to make novel inferences, and storing a veridical copy of past experience. However, the neural mechanisms that control this trade-off remain unknown. Using a cross-scale approach that combines a pharmacological intervention in humans with neural network modelling, we show that the neuromodulator noradrenaline elicits a significant ‘spread of association’ across hippocampal cognitive maps. This neural spread of association can be explained by changes in synaptic plasticity that predict overgeneralisation in behaviour. Thus, elevated noradrenaline during learning increases the ‘smoothing kernel’ for plasticity across the cognitive map, allowing disparate memories to become linked and distorted.
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Data availability
All data generated and analysed during this study are included in the manuscript and supporting files. Source data are provided with this paper. Group-level data is available from the MRC BNDU Data Sharing Platform via https://doi.org/10.60964/BNDU-Z7QY-JP81. The following dataset was generated: fMRI data. MRS data. Pupillometry data. Behavioural data Source data are provided with this paper.
Code availability
Upon publication the code used for data analysis will be available from the MRC BNDU Data Sharing Platform via https://doi.org/10.60964/BNDU-Z7QY-JP81. Upon publication the code used for the spiking neural network model will be available from the MRC BNDU Data Sharing Platform via https://doi.org/10.60964/BNDU-9B3H-A961, and is also available on https://github.com/p-rakriti/koolschijn_et_al.
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Acknowledgements
We would like to thank Chamith Halahakoon, Phil Cowen, Angharad De Cates, Beata Godlewska, Riccardo De Giorgi, Katherine Smith and Edoardo Ostinelli for enabling this study by providing medical cover. We would like to thank Douglas F. Tomé and Everton J. Agnes for their guidance and advice with earlier versions of the neural network model. We would like to thank Rob Froemke for helpful discussion when preparing the experiments. We thank Leonie Glitz and Valentina Mancini for comments on an earlier version of the manuscript. R.S.K. was supported by an EPSRC/MRC-funded studentship (EP/L016052/1). P.P. was supported by the Cambridge Trust, Trinity Henry Barlow Scholarship and Trinity Hall Brockhouse Scholarship. L.C. is supported by the Foundation for Science and Technology (FCT) (Portuguese State Budget: UID/PSI/01662/2020; Research fellowship: 2021.00415.CEECIND). W.T.C. is funded by the Wellcome Trust [225924/Z/22/Z]. H.C.B. is supported by a UKRI Future Leaders Fellowship (MR/W008939/1) and the Wellcome Institutional Strategic Support Fund. H.C.B. and J.X.O. are supported by the Medical Research Council (MR/W01971X/1). The study was supported by the NIHR Oxford Health Biomedical Research Centre (NIHR203316). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z and 203139/A/16/Z). This research was funded in part by the Wellcome Trust. For the purpose of open access, the author(s) have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
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All authors contributed to the preparation of the manuscript. R.S.K., J.X.O., and H.C.B. designed the study. R.S.K. and H.C.B. acquired ethics for the study. L.C. and R.S.K. prepared and administered the double-blind procedure. M.B. provided clinical support for the study. R.S.K. acquired the data. W.C. and R.S.K. developed the MRS sequence and analysed the MRS data. R.S.K. analysed the behavioural data, pupillometry data and fMRI data with supervision from J.X.O. and H.C.B. X.P. assisted with the fMRI analyses. P.P. generated all neural network simulations with supervision from T.P.V. R.S.K., P.P., and H.C.B. prepared the figures.
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M.B. has received travel expenses from Lundbeck for attending conferences and has acted as a consultant for J&J, Novartis, Boehringher and CHDR. He previously owned shares in P1vital Ltd. All other authors declare no competing interests.
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Koolschijn, R.S., Parthasarathy, P., Browning, M. et al. Noradrenaline causes a spread of association in the hippocampal cognitive map. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70659-x
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DOI: https://doi.org/10.1038/s41467-026-70659-x
