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A dual role of hippocampal perineuronal nets in plasticity and protection is revealed by improvement and impairment of diet-induced memory dysfunction

Neuropsychopharmacology (2026)Cite this article

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Abstract

Alterations to perineuronal nets (PNNs) are linked to cognitive deficits observed in multiple neuropsychiatric and neurodegenerative conditions. PNNs are proposed both to limit neuronal plasticity and to protect neuronal populations critical for cognitive function. Here, we assessed these two distinct proposed functions of PNNs in the same experimental procedure, varying only the timing of PNN manipulation. Enzymatic degradation of hippocampal PNNs 4 weeks after an obesogenic high-fat high-sugar (HFHS) diet – which causes hippocampal-dependent memory impairments – restored memory performance, demonstrating a key role of PNNs in plasticity. In contrast, degradation of hippocampal PNNs prior to HFHS diet exacerbated memory deficits, demonstrating PNNs’ role in neuroprotection. Because PNNs primarily surround PV+ neurons (PVNs), we hypothesized that the mechanism underlying these effects of PNN degradation would involve, at least in part, alterations in hippocampal PVN function. Thus, to see whether PNN degradation alters the function of hippocampal PVNs, we took fiber photometry measurements across multi-day timescales and found that hippocampal PNN degradation alters calcium events in PVNs. We then went on to explicitly manipulate PVNs and found that chemogenetic inhibition of hippocampal PVNs in mice on a standard diet impaired memory performance, and activation of hippocampal PVNs in mice on a HFHS diet restored memory performance, bidirectional effects that mirror the bidirectional effects of PNN degradation. Taken together, these findings support the dual plasticity and protection hypothesis of PNN function, provide evidence that key mechanisms of memory involve the interaction of PNNs and PVNs, and point to PNNs as a potential therapeutic target in cognitive decline.

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Fig. 1: Degradation of hippocampal PNNs restores memory in HFHS-diet mice and enhances memory in control-diet mice.
Fig. 2: Degradation of hippocampal PNNs before HFHS diet consumption exacerbates memory impairment in HFHS-diet mice.
Fig. 3: Calcium recordings from hippocampal PVNs before (baseline) and after several days post-ChABC infusion.
Fig. 4: Chemogenetic inhibition of hippocampal PVNs impairs performance of the s-SLR task.
Fig. 5: Chemogenetic excitation of hippocampal PVNs reverses HFHS diet-induced memory deficits, and enhances performance in control diet mice.

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Experimental data from these studies are available at https://osf.io/ujg7w/?view_only=10f8d31b8ede45c39d447ca4dd582a3f.

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Acknowledgements

We thank Prof Vania Prado, Prof Marco Prado and the Robarts Rodent Core for their assistance and acquisition of the transgenic mice, Mr Chris Fodor for his assistance with genotyping and colony breeding, and Prof Anthony Hannan for his feedback on the manuscript.

Funding

This research was supported by BrainsCAN at Western University through the Canada First Research Excellence Fund (CFREF) and the Natural Sciences and Engineering Research Council (NSERC). LMS is the Canada Research Chair in Translational Cognitive Neuroscience and TJB is the Western Research Chair in Behavioral Neuroscience. ACR received funding from the Australian Research Council (DP180101974).

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Amy C. Reichelt, Ahmed M. Hashad, Cecilia P. Kramar, Oren Princz-Lebel, Wataru Inoue, Timothy J. Bussey & Lisa M. Saksida

  2. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, On, Canada

    Amy C. Reichelt, Ahmed M. Hashad, Olivia R. Ghosh-Swaby, Miguel Skirzewski, Gavin A. Scott, Meira Machado, Cecilia P. Kramar, Oren Princz-Lebel, Wataru Inoue, Timothy J. Bussey & Lisa M. Saksida

  3. Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia

    Amy C. Reichelt

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    Ahmed M. Hashad

  5. Western Institute for Neuroscience, Western University, London, ON, Canada

    Olivia R. Ghosh-Swaby, Miguel Skirzewski, Timothy J. Bussey & Lisa M. Saksida

  6. Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada

    Cecilia P. Kramar

  7. Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Wataru Inoue

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  1. Amy C. Reichelt
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Contributions

ACR, TJB, LMS, CPK, AMH and WI designed the experiments. ACR, AMH, MGS and OGS performed the experiments. ACR, OPL, GAS, and MM completed the immunohistochemistry and microscopy validation. ACR, OGS, TJB, LMS, AMH and WI wrote the manuscript. OGS edited and revised the manuscript and figures.

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Correspondence to Olivia R. Ghosh-Swaby.

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Reichelt, A.C., Hashad, A.M., Ghosh-Swaby, O.R. et al. A dual role of hippocampal perineuronal nets in plasticity and protection is revealed by improvement and impairment of diet-induced memory dysfunction. Neuropsychopharmacol. (2026). https://doi.org/10.1038/s41386-026-02343-z

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