Abstract
Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.
Highlights
Accurate memory requires both recognition of previously encountered stimuli and the ability to distinguish between similar, but distinct, events[1]
Taking advantage of distinct susceptibility to age and other constitutional sources of variability of dentate gyrus and CA3 volume, we investigate the function of the dentate gyrus and CA3 across a large number of individuals
The effect of age is significant in all subfields and the total hippocampus for similar item accuracy, which we use as our measure of behavioural pattern separation
Summary
Accurate memory requires both recognition of previously encountered stimuli and the ability to distinguish between similar, but distinct, events (pattern separation)[1]. Animal work suggests that CA3 and dentate gyrus enable accurate object recognition and pattern separation respectively. One simplified view of this network is that pattern separation in the dentate gyrus helps separate memories of similar events to protect against erroneous object recognition in CA3. Confirmation of these roles for dentate gyrus and CA3 in humans is currently lacking. We exploit the principle that aging is associated with differential performance on cognitive tasks – with memory biased away from pattern separation towards pattern completion[11,12]. We expect that pure object recognition will be CA3-dependent and CA3 volume will predict object recognition performance more precisely than dentate gyrus volume
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