RT Journal Article
SR Electronic
T1 Proximal CA3 is the primary locus of age-related pattern separation deficits in rats
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.14.460329
DO 10.1101/2021.09.14.460329
A1 Heekyung Lee
A1 Arjuna Tilekeratne
A1 Nick Lukish
A1 Zitong Wang
A1 Scott Zeger
A1 Michela Gallagher
A1 James J. Knierim
YR 2021
UL http://biorxiv.org/content/early/2021/09/16/2021.09.14.460329.abstract
AB 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 StatementM.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.