Loss of functional heterogeneity along the CA3 transverse axis in aging

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.

Cell numbers in the reflected blade of CA3 and their relation to other hippocampal principal cell populations across seven species

“…Autoassociative connections are relatively sparse in proximal CA3 (Sun et al, 2017), which anatomically reflects the shift from pattern completion to pattern separation. Not surprisingly, functional deficits following proximal CA3 lesions resemble dentate lesions (Hunsaker et al, 2008), and, interestingly, hyperactivity restricted to proximal CA3 is involved in age-related memory impairments (Lee et al, 2021). The tight functional integration of the dentate and proximal CA3 that some of these studies argue for (GoodSmith et al, 2019;Lee et al, 2020) may be further developed in species with a reflected blade, an argument that has been made before for the primate hippocampus (Lim et al, 1997a).…”