Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task – Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20–89. When we classify those individuals ages 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.

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.

Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for "representational rigidity" in older adults' dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.L ong-term memory function is commonly known to deteriorate with increasing age. One of the sites that undergo the earliest changes is the hippocampus (1, 2), which has a well-known role in learning new facts and remembering events (3). Recently, electrophysiological recording studies in aged rodents have shed light on some of the possible neural mechanisms in the hippocampus that underlie this decline (1). These studies have demonstrated "rigidity" in aged CA3 place cell firing patterns in similar environments. In contrast to young CA3 place cells, which readily remap and shift their representations in these environments, aged CA3 place cells retain their original fields despite the changes in the environment. These data strongly suggest that aging is associated with a diminished capacity for pattern separation (learning new information by decorrelating similar inputs to avoid interference) and an increased propensity for pattern completion (retrieval of previously stored information from a partial cue), and further suggest that this shift could be the result of a functional imbalance in the hippocampal dentate gyrus (DG) and CA3 network.The role of hippocampal subfields in these key processes has long been hypothesized in computational models (4-7). The models suggest that the DG granule cells are capable of performing especially strong pattern separation on the distributed representations arriving from layer II entorhinal neurons, projecting this signal onto the CA3 subfield of the hippocampus via the strong mossy fiber pathway. Empirical evidence for the involvement of the 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 studies using DG-specific ibotenic acid lesions (14), as well as genetic NMDA receptor knockouts (15), have additionally shown that the DG is critical for, and the likely ...

Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfieldlevel region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input.