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Age-Related Memory Deficits Linked to Circuit-Specific Disruptions in The Age-related memory deficits linked to circuit-specific disruptions in the hippocampus Michael A. Yassaa,b,c,1, Aaron T. Mattfeldb,c, Shauna M. Starkb,c, and Craig E. L. Starkb,c,1 aDepartment of Psychological and Brain Sciences, The Johns Hopkins University, Baltimore, MD 21218; bDepartment of Neurobiology and Behavior, University of California, Irvine, CA 92697; and cCenter for Neurobiology of Learning and Memory, Irvine, CA 92697 Edited by Edward E. Smith, Columbia University, New York, NY, and approved April 15, 2011 (received for review January 27, 2011) Converging data from rodents and humans have demonstrated an have more difficulties learning new information and may only age-related decline in pattern separation abilities (the ability to encode the “gist” and not as many event details as young adults. discriminate among similar experiences). Several studies have pro- We (20) as well as others (21) have tested this hypothesis more posed the dentate and CA3 subfields of the hippocampus as the explicitly in older adults by using an object discrimination task. potential locus of this change. Specifically, these studies identified Consistent with the predictions from the rodent work, both rigidity in place cell remapping in similar environments in the CA3. studies found that older adults tended to be biased more toward We used high-resolution fMRI to examine activity profiles in the completion at the expense of separation. We also demonstrated dentate gyrus and CA3 in young and older adults as stimulus that these behavioral impairments were correlated with hippo- similarity was incrementally varied. We report evidence for “repre- campal DG/CA3 network hyperactivity (20), consistent with the sentational rigidity” in older adults’ dentate/CA3 that is linked to finding in the rodent that aged CA3 place cells exhibit generally behavioral discrimination deficits. Using ultrahigh-resolution diffu- elevated firing rates across novel and familiar environments (22). sion imaging, we quantified both the integrity of the perforant In this investigation, we hypothesized that the pattern separa- path as well as dentate/CA3 dendritic changes and found that both tion signals exhibited by the DG/CA3 would be diminished with were correlated with dentate/CA3 functional rigidity. These results age for highly similar, but not dissimilar inputs (our techniques do highlight structural and functional alterations in the hippocampal not allow us to isolate DG and CA3 activity). Consistent with our network that predict age-related changes in memory function and predictions, we found no differences in DG/CA3 fMRI activity present potential targets for intervention. between young and older adults when stimuli were made very NEUROSCIENCE different. However, as stimuli were made more similar, the DG/ medial temporal lobe | diffusion tensor imaging | functional MRI | CA3 response was weakened in older adults (consistent with generalization | pattern completion pattern completion) but remained high in young adults, indicating that older adults’ DG/CA3 had an attenuated separation response ong-term memory function is commonly known to deteriorate to the lures. We refer to this change as a representational rigidity, fi Lwith increasing age. One of the sites that undergo the earliest which is operationally de ned as the requirement for increased changes is the hippocampus (1, 2), which has a well-known role in dissimilarity before stimuli can be orthogonalized, thus showing learning new facts and remembering events (3). Recently, electro- greater resistance to change. Critically, the extent of this rigidity fi physiological recording studies in aged rodents have shed light on predicted performance de cits in a behavioral discrimination task some of the possible neural mechanisms in the hippocampus that similar to the one used in our previous work (20). underlie this decline (1). These studies have demonstrated “rigidity” Further, to evaluate the structural correlates of the rigidity we in aged CA3 place cell firing patterns in similar environments. In observed in the DG/CA3 functional network, we used ultrahigh contrast to young CA3 place cells, which readily remap and shift resolution microstructural diffusion tensor imaging (msDTI) their representations in these environments, aged CA3 place cells techniques developed in our laboratory (23) to assess potential changes in diffusion properties within hippocampal subfield gray retain their original fields despite the changes in the environment. matter. We found a correlation between left DG/CA3 functional These data strongly suggest that aging is associated with a dimin- rigidity and the same region’s fractional anisotropy (a measure of ished capacity for pattern separation (learning new information by directional diffusion). Directional diffusion in gray matter is decorrelating similar inputs to avoid interference) and an increased thought to be an index of dendritic integrity (23, 24). Thus, these propensity for pattern completion (retrieval of previously stored results suggest that structural dendritic changes in this region may information from a partial cue), and further suggest that this shift contribute to the functional impairments observed, consistent with could be the result of a functional imbalance in the hippocampal the idea that the dentate and CA3 in particular are selectively vul- dentate gyrus (DG) and CA3 network. nerable to the aging process, because no such relationship was The role of hippocampal subfields in these key processes has long fi – found in other sub elds. been hypothesized in computational models (4 7). The models Next, we tested another key prediction of the model proposed suggest that the DG granule cells are capable of performing es- by Wilson et al. (1), namely that the degraded perforant path pecially strong pattern separation on the distributed representa- input to the DG and CA3 is linked to pattern separation deficits. tions arriving from layer II entorhinal neurons, projecting this The perforant path provides the primary afferent input to the fi signal onto the CA3 sub eld of the hippocampus via the strong dentate and CA3 from layer II entorhinal cortical neurons (25). fi mossy ber pathway. Empirical evidence for the involvement of the Studies in the rodent have shown that this pathway is essential DG and CA3 in pattern separation has been demonstrated by using electrophysiological recordings (8–10), immediate-early genes (11), and high-resolution functional MRI in humans (12, 13). Ablation Author contributions: M.A.Y. and C.E.L.S. designed research; M.A.Y., A.T.M., S.M.S., and studies using DG-specific ibotenic acid lesions (14), as well as ge- C.E.L.S. performed research; M.A.Y., A.T.M., S.M.S., and C.E.L.S. analyzed data; and netic NMDA receptor knockouts (15), have additionally shown M.A.Y., A.T.M., and C.E.L.S. wrote the paper. that the DG is critical for, and the likely locus of pattern separation. The authors declare no conflict of interest. Recent evidence also indicates that neurogenesis in the DG may be This article is a PNAS Direct Submission. particularly important for pattern separation (16–19). 1To whom correspondence may be addressed. E-mail: [email protected] or [email protected]. The shift from pattern separation to pattern completion with This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. age is hypothesized to be one of the reasons why older adults 1073/pnas.1101567108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1101567108 PNAS Early Edition | 1of6 Downloaded by guest on September 25, 2021 for normal hippocampal function (26) and documented its deg- regarding circularity and double dipping (32), we used data from two radation with advancing age (23, 27–31). Here, we tested the previously collected samples to define repetition-sensitive regions of hypothesis that the network imbalance we observed in the fMRI interest (ROIs) in the hippocampus and then applied these ROI data may be the result of an age-related degradation in the per- masks to our new, independent sample to investigate the effect of forant path. To accomplish this goal, we used msDTI to visualize varying the degree of stimulus similarity on activity for lures. and quantify the perforant path diffusion signal as an in vivo Based on extensive behavioral investigations (20), lures were correlate of this pathway’s integrity. We found that perforant path binned according to their mnemonic similarity, allowing us to integrity was tightly correlated with the extent of left DG/CA3 conduct a parametric investigation of DG/CA3 input/output rigidity. In addition, perforant path integrity itself was predictive transfer functions. In our recent work (13), we found that in a of performance of older adults on a behavioral discrimination population of young adults, activity in a repetition-sensitive por- task. A potential functional consequence of a degraded perforant tion of DG/CA3 increased markedly with even small amounts of path is a decrement in the functional correlations between the change in the input (highly similar lures) and remained constantly entorhinal cortex (EC) and the DG/CA3. To evaluate this possi- elevated as lure similarity increased. We observed this constant bility, we performed a seed-style functional connectivity analysis activity consistent with strong separation again here in young at the subfield level. The functional coupling of the DG/CA3 with adults in the left DG/CA3 (Fig. 2B). Older adults, however, had the entorhinal cortex was highly correlated with the rigidity in the an attenuated left DG/CA3 separation response to the lures such CA3, suggesting that the level of rigidity in the DG/CA3 may be that separation signals were only noted on the highly dissimilar C related to degradation in the signaling between the entorhinal lures (Fig. 2 ). This representational rigidity was consistent with A cortex and the hippocampus. the theoretical predictions shown in Fig. 2 . × These data support the notion that age-related changes in the We conducted a 2 5 ANOVA with group (old vs.
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