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Proximal CA3 is the primary locus of age-related pattern separation deficits in rats

Heekyung Lee, Arjuna Tilekeratne, Nick Lukish, Zitong Wang, Scott Zeger, Michela Gallagher, James J. Knierim
doi: https://doi.org/10.1101/2021.09.14.460329
Heekyung Lee
1Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218
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  • For correspondence: heekyung@jhu.edu jknierim@jhu.edu
Arjuna Tilekeratne
1Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218
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Nick Lukish
1Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218
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Zitong Wang
2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205
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Scott Zeger
2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205
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Michela Gallagher
3Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD
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James J. Knierim
1Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, 21218
3Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD
4Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205
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  • For correspondence: heekyung@jhu.edu jknierim@jhu.edu
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Abstract

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. While the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, with proximal CA3 supporting pattern separation and distal CA3 supporting pattern completion. We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. When the environmental similarity was high (e.g., altered cues or altered environment shapes in the same room), Y and AU rats showed more orthogonalized representations in proximal CA3 than in distal CA3, consistent with prior studies showing a functional dissociation along the transverse axis of CA3. In contrast, AI rats showed less orthogonalization in proximal CA3 than Y and AU rats but showed more normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. When the environmental similarity was low (e.g., recordings were done in different rooms), representations in proximal and distal CA3 remapped in all rats, showing that AI rats are able to dissociate representations when inputs show greater dissimilarity. These results provide evidence that the aged-related bias towards pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis and, furthermore, that proximal CA3 is the primary locus of this age-related dysfunction in neural coding.

Competing Interest Statement

M.G. is the founder of AgeneBio Incorporated, a biotechnology company that is dedicated to discovery and development of therapies to treat cognitive impairment. M.G. has a financial interest in the company and is an inventor on Johns Hopkins University's intellectual property that is licensed to AgeneBio. Otherwise, M.G. has had no consulting relationship with other public or private entities in the past three years and has no other financial holdings that could be perceived as constituting a potential conflict of interest. All conflicts of interest are managed by Johns Hopkins University. All other authors have nothing to disclose.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 16, 2021.
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Proximal CA3 is the primary locus of age-related pattern separation deficits in rats
Heekyung Lee, Arjuna Tilekeratne, Nick Lukish, Zitong Wang, Scott Zeger, Michela Gallagher, James J. Knierim
bioRxiv 2021.09.14.460329; doi: https://doi.org/10.1101/2021.09.14.460329
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Proximal CA3 is the primary locus of age-related pattern separation deficits in rats
Heekyung Lee, Arjuna Tilekeratne, Nick Lukish, Zitong Wang, Scott Zeger, Michela Gallagher, James J. Knierim
bioRxiv 2021.09.14.460329; doi: https://doi.org/10.1101/2021.09.14.460329

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