Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults

Abstract

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age-related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age-related neural changes in the human hippocampus using high-resolution (1.5 mm isotropic) BOLD fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared to young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.

Age-related memory deficits linked to circuit-specific disruptions in the hippocampus

“…Consistent with the predictions from the rodent work, both studies found that older adults tended to be biased more toward completion at the expense of separation. We also demonstrated that these behavioral impairments were correlated with hippocampal DG/CA3 network hyperactivity (20), consistent with the finding in the rodent that aged CA3 place cells exhibit generally elevated firing rates across novel and familiar environments (22).…”

“…In this task, participants saw novel, repeated and similar lure items and were asked to indicate whether the item was "old," "similar," or "new." Our previous work (20) has shown that older adults have a diminished "separation bias" on this task compared with young adults (i.e., they were less likely to call lure items similar and more likely to call them old). We replicated this effect here (Fig.…”

“…We refer to this change as a representational rigidity, which is operationally defined as the requirement for increased dissimilarity before stimuli can be orthogonalized, thus showing greater resistance to change. Critically, the extent of this rigidity predicted performance deficits in a behavioral discrimination task similar to the one used in our previous work (20).…”

“…Based on extensive behavioral investigations (20), lures were binned according to their mnemonic similarity, allowing us to conduct a parametric investigation of DG/CA3 input/output transfer functions. In our recent work (13), we found that in a population of young adults, activity in a repetition-sensitive portion of DG/CA3 increased markedly with even small amounts of change in the input (highly similar lures) and remained constantly elevated as lure similarity increased.…”

“…We (20) as well as others (21) have tested this hypothesis more explicitly in older adults by using an object discrimination task. Consistent with the predictions from the rodent work, both studies found that older adults tended to be biased more toward completion at the expense of separation.…”