An Information-Geometric Formulation of Pattern Separation and Evaluation of Existing Indices.

Pattern separation is a computational process by which dissimilar neural patterns are generated from similar input patterns. We present an information-geometric formulation of pattern separation, where a pattern separator is modeled as a family of statistical distributions on a manifold. Such a manifold maps an input (i.e., coordinates) to a probability distribution that generates firing patterns. Pattern separation occurs when small coordinate changes result in large distances between samples from the corresponding distributions. Under this formulation, we implement a two-neuron system whose probability law forms a three-dimensional manifold with mutually orthogonal coordinates representing the neurons' marginal and correlational firing rates. We use this highly controlled system to examine the behavior of spike train similarity indices commonly used in pattern separation research. We find that all indices (except scaling factor) are sensitive to relative differences in marginal firing rates, but no index adequately captures differences in spike trains that result from altering the correlation in activity between the two neurons. That is, existing pattern separation metrics appear (A) sensitive to patterns that are encoded by different neurons but (B) insensitive to patterns that differ only in relative spike timing (e.g., synchrony between neurons in the ensemble).

A response time model of the three-choice Mnemonic Similarity Task provides stable, mechanistically interpretable individual-difference measures.

Introduction: The Mnemonic Similarity Task (MST) is a widely used measure of individual tendency to discern small differences between remembered and presently presented stimuli. Significant work has established this measure as a reliable index of neurological and cognitive dysfunction and decline. However, questions remain about the neural and psychological mechanisms that support performance in the task. Methods: Here, we provide new insights into these questions by fitting seven previously-collected MST datasets (total N = 519), adapting a three-choice evidence accumulation model (the Linear Ballistic Accumulator). The model decomposes choices into automatic and deliberative components. Results: We show that these decomposed processes both contribute to the standard measure of behavior in this task, as well as capturing individual variation in this measure across the lifespan. We also exploit a delayed test/re-test manipulation in one of the experiments to show that model parameters exhibit improved stability, relative to the standard metric, across a 1 week delay. Finally, we apply the model to a resting-state fMRI dataset, finding that only the deliberative component corresponds to off-task co-activation in networks associated with long-term, episodic memory. Discussion: Taken together, these findings establish a novel mechanistic decomposition of MST behavior and help to constrain theories about the cognitive processes that support performance in the task.

Dissociations in perceptual discrimination following selective damage to the dentate gyrus versus CA1 subfield of the hippocampus.

The hippocampus (HPC) is well-known for its involvement in declarative (consciously accessible) memory, but there is evidence that it may also play a role in complex perceptual discrimination. Separate research has demonstrated separable contributions of HPC subregions to component memory processes, with the dentate gyrus (DG) required for mnemonic discrimination of similar inputs and the CA1 subfield required for retention and retrieval, but contributions of these subregions to perceptual processes is understudied. The current study examined the nature and extent of a double dissociation between the dentate gyrus (DG) to discrimination processes and CA1 subfield to retention/retrieval by testing two unique individuals with bilateral damage to the DG (case BL) and CA1 (case BR). We tested BL and BR on a wide range of standardized neuropsychological tests to assess information encoding and retention/retrieval and co-opted many measures to assess perceptual discrimination. Compared to normative data, BL exhibited performance below expectations on most measures requiring perceptual discrimination and on measures of encoding but demonstrated intact retention. Conversely, BR showed no difficulties with perceptual discrimination or verbal encoding but exhibited poor verbal retention, as well as poor encoding and retention of spatial/integrative tasks (e.g., object in a location). These results indicate that, despite its prominent role in memory, the DG is necessary for perceptual discrimination and encoding, whereas CA1 is necessary for retention/retrieval and encoding of spatial information. The pattern of results highlights the critical nature of individual case studies in the nuanced understanding of HPC subfield contributions to different memory processes, as well as the utility of repurposing neuropsychological measures to capture individual differences.

Effect of adult-born immature granule cells on pattern separation in the hippocampal dentate gyrus.

Young immature granule cells (imGCs) appear via adult neurogenesis in the hippocampal dentate gyrus (DG). In comparison to mature GCs (mGCs) (born during development), the imGCs exhibit two competing distinct properties such as high excitability (increasing activation degree) and low excitatory innervation (reducing activation degree). We develop a spiking neural network for the DG, incorporating both the mGCs and the imGCs. The mGCs are well known to perform "pattern separation" (i.e., a process of transforming similar input patterns into less similar output patterns) to facilitate pattern storage in the hippocampal CA3. In this paper, we investigate the effect of the young imGCs on pattern separation of the mGCs. The pattern separation efficacy (PSE) of the mGCs is found to vary through competition between high excitability and low excitatory innervation of the imGCs. Their PSE becomes enhanced (worsened) when the effect of high excitability is higher (lower) than the effect of low excitatory innervation. In contrast to the mGCs, the imGCs are found to perform "pattern integration" (i.e., making association between dissimilar patterns). Finally, we speculate that memory resolution in the hippocampal CA3 might be optimally maximized via mixed cooperative encoding through pattern separation and pattern integration.

Effects of the Regular Use of Virtual Environments on Spatial Navigation and Memory.

Introduction: The cognitive effects of video games have garnered increasing attention due to their potential applications in cognitive rehabilitation and evaluation. However, the underlying mechanisms driving these cognitive modifications remain poorly understood. Objectives: This study investigates the fundamental mnemonic processes of spatial navigation, pattern separation, and recognition memory, closely associated with the hippocampus. Our objective is to elucidate the interaction of these cognitive processes and shed light on rehabilitation mechanisms that could inform the design of video games aimed at stimulating the hippocampus. Method: In this study, we assessed 48 young adults, including both video game players and non-players. We utilized virtual reality and cognitive tasks such as the Lobato Virtual Water Maze and the Mnemonic Similarity Task to evaluate their cognitive abilities. Results: Our key findings highlight that gamers exhibit heightened pattern separation abilities and demonstrate quicker and more accurate spatial learning, attributed to the cognitive stimulation induced by video games. Additionally, we uncovered a significant relationship between spatial memory, guided by environmental cues, and pattern separation, which serves as the foundation for more efficient spatial navigation. Conclusions: These results provide valuable insights into the cognitive impact of video games and offer potential for monitoring changes in rehabilitation processes and early signs of cognitive decline through virtual reality-based assessments. Ultimately, we propose that examining the relationships between cognitive processes represents an effective method for evaluating neurodegenerative conditions, offering new possibilities for early diagnosis and intervention.

Discrimination of semantically similar verbal memory traces is affected in healthy aging.

Mnemonic discrimination of highly similar memory traces is affected in healthy aging via changes in hippocampal pattern separation-i.e., the ability of the hippocampus to orthogonalize highly similar neural inputs. The decline of this process leads to a loss of episodic specificity. Because previous studies have almost exclusively tested mnemonic discrimination of visuospatial stimuli (e.g., objects or scenes), less is known about age-related effects on the episodic specificity of semantically similar traces. To address this gap, we designed a task to assess mnemonic discrimination of verbal stimuli as a function of semantic similarity based on word embeddings. Forty young (Mage = 21.7 years) and 40 old adults (Mage = 69.8 years) first incidentally encoded adjective-noun phrases, then performed a surprise recognition test involving exactly repeated and highly similar lure phrases. We found that increasing semantic similarity negatively affected mnemonic discrimination in both age groups, and that compared to young adults, older adults showed worse discrimination at medium levels of semantic similarity. These results indicate that episodic specificity of semantically similar memory traces is affected in aging via less efficient mnemonic operations and strengthen the notion that mnemonic discrimination is a modality-independent process supporting memory specificity across representational domains.

Adult Neurogenesis, Context Encoding, and Pattern Separation: A Pathway for Treating Overgeneralization.

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Contribution of the lateral occipital and parahippocampal cortices to pattern separation of objects and contexts.

Contextual features are integral to episodic memories; yet, we know little about context effects on pattern separation, a hippocampal function promoting orthogonalization of overlapping memory representations. Recent studies suggested that various extrahippocampal brain regions support pattern separation; however, the specific role of the parahippocampal cortex-a region involved in context representation-in pattern separation has not yet been studied. Here, we investigated the contribution of the parahippocampal cortex (specifically, the parahippocampal place area) to context reinstatement effects on mnemonic discrimination, using functional magnetic resonance imaging. During scanning, participants saw object images on unique context scenes, followed by a recognition task involving the repetitions of encoded objects or visually similar lures on either their original context or a lure context. Context reinstatement at retrieval improved item recognition but hindered mnemonic discrimination. Crucially, our region of interest analyses of the parahippocampal place area and an object-selective visual area, the lateral occipital cortex indicated that while during successful mnemonic decisions parahippocampal place area activity decreased for old contexts compared to lure contexts irrespective of object novelty, lateral occipital cortex activity differentiated between old and lure objects exclusively. These results imply that pattern separation of contextual and item-specific memory features may be differentially aided by scene and object-selective cortical areas.

Memory's gatekeeper: The role of PFC in the encoding of congruent events.

Theoretical models conventionally portray the consolidation of memories as a slow process that unfolds during sleep. According to the classical Complementary Learning Systems theory, the hippocampus (HPC) rapidly changes its connectivity during wakefulness to encode ongoing events and create memory ensembles that are later transferred to the prefrontal cortex (PFC) during sleep. However, recent experimental studies challenge this notion by showing that new information consistent with prior knowledge can be rapidly consolidated in PFC during wakefulness and that PFC lesions disrupt the encoding of congruent events in the HPC. The contributions of the PFC to memory encoding have therefore largely been overlooked. Moreover, most theoretical frameworks assume random and uncorrelated patterns representing memories, disregarding the correlations between our experiences. To address these shortcomings, we developed a HPC-PFC network model that simulates interactions between the HPC and PFC during the encoding of a memory (awake stage), and subsequent consolidation (sleeping stage) to examine the contributions of each region to the consolidation of novel and congruent memories. Our results show that the PFC network uses stored memory "schemas" consolidated during previous experiences to identify inputs that evoke congruent patterns of activity, quickly integrate it into its network, and gate which components are encoded in the HPC. More specifically, the PFC uses GABAergic long-range projections to inhibit HPC neurons representing input components correlated with a previously stored memory "schema," eliciting sparse hippocampal activity during exposure to congruent events, as it has been experimentally observed.

Context and space coding in mossy cell population activity.

The dentate gyrus plays a key role in the discrimination of memories by segregating and storing similar episodes. Whether hilar mossy cells, which constitute a major excitatory principal cell type in the mammalian hippocampus, contribute to this decorrelation function has remained largely unclear. Using two-photon calcium imaging of head-fixed mice performing a spatial virtual reality task, we show that mossy cell populations robustly discriminate between familiar and novel environments. The degree of discrimination depends on the extent of visual cue differences between contexts. A context decoder revealed that successful environmental classification is explained mainly by activity difference scores of mossy cells. By decoding mouse position, we reveal that in addition to place cells, the coordinated activity among active mossy cells markedly contributes to the encoding of space. Thus, by decorrelating context information according to the degree of environmental differences, mossy cell populations support pattern separation processes within the dentate gyrus.

Effects of Age on Cross-Cultural Differences in the Neural Correlates of Memory Retrieval.

Culture can shape memory, but little research investigates age effects. The present study examines the neural correlates of memory retrieval for old, new, and similar lures in younger and older Americans and Taiwanese. Results show that age and culture impact discrimination of old from new items. Taiwanese performed worse than Americans, with age effects more pronounced for Taiwanese. Americans activated the hippocampus for new more than old items, but pattern of activity for the conditions did not differ for Taiwanese, nor did it interact with age. The engagement of left inferior frontal gyrus (LIFG) differed across cultures. Patterns of greater activity for old (for Americans) or new (for Taiwanese) items were eliminated with age, particularly for older Americans. The results are interpreted as reflecting cultural differences in orientation to novelty vs. familiarity for younger, but not older, adults, with the LIFG supporting interference resolution at retrieval. Support is not as strong for cultural differences in pattern separation processes. Although Americans had higher levels of memory discrimination than Taiwanese and engaged the LIFG for correct rejections more than false alarms, the patterns of behavior and neural activity did not interact with culture and age. Neither culture nor age impacted hippocampal activity, which is surprising given the region's role in pattern separation. The findings suggest ways in which cultural life experiences and concomitant information processing strategies can contribute to consistent effects of age across cultures or contribute to different trajectories with age in terms of memory.

Hippocampus-to-amygdala pathway drives the separation of remote memories of related events.

The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this function remains elusive. Here, we show in rats that recent memories of two closely timed auditory fear events share overlapping neuronal ensembles in the basolateral amygdala (BLA) and are functionally linked. However, remote memories have reduced neuronal overlap and are functionally independent. The activity of parvalbumin (PV)-expressing neurons in the BLA plays a crucial role in forming separate remote memories. Chemogenetic blockade of PV preserves individual remote memories but prevents their segregation, resulting in reciprocal associations. The hippocampus drives this process through specific excitatory connections with BLA GABAergic interneurons. These findings provide insights into the neuronal mechanisms that minimize the overlap between distinct remote memories and enable the retrieval of related memories separately.

Increased flexibility of CA3 memory representations following environmental enrichment.

Environmental enrichment (EE) improves memory, particularly the ability to discriminate similar past experiences.1,2,3,4,5,6 The hippocampus supports this ability via pattern separation, the encoding of similar events using dissimilar memory representations.7 This is carried out in the dentate gyrus (DG) and CA3 subfields.8,9,10,11,12 Upregulation of adult neurogenesis in the DG improves memory through enhanced pattern separation.1,2,3,4,5,6,11,13,14,15,16 Adult-born granule cells (abGCs) in DG are suggested to contribute to pattern separation by driving inhibition in regions such as CA3,13,14,15,16,17,18 leading to sparser, nonoverlapping representations of similar events (although a role for abGCs in driving excitation in the hippocampus has also been reported16). Place cells in the hippocampus contribute to pattern separation by remapping to spatial and contextual alterations to the environment.19,20,21,22,23,24,25,26,27 How spatial responses in CA3 are affected by EE and input from increased numbers of abGCs in DG is, however, unknown. Here, we investigate the neural mechanisms facilitating improved memory following EE using associative recognition memory tasks that model the automatic and integrative nature of episodic memory. We find that EE-dependent improvements in difficult discriminations are related to increased neurogenesis and sparser memory representations across the hippocampus. Additionally, we report for the first time that EE changes how CA3 place cells discriminate similar contexts. CA3 place cells of enriched rats show greater spatial tuning, increased firing rates, and enhanced remapping to contextual changes. These findings point to more precise and flexible CA3 memory representations in enriched rats, which provides a putative mechanism for EE-dependent improvements in fine memory discrimination.

Maladaptation of dentate gyrus mossy cells mediates contextual discrimination deficit after traumatic stress.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

Differential contributions of the hippocampal dentate gyrus and CA1 subfield to mnemonic discrimination.

Evidence suggests that individual hippocampal subfields are preferentially involved in various memory-related processes. Here, we demonstrated dissociations in these memory processes in two unique individuals with near-selective bilateral damage within the hippocampus, affecting the dentate gyrus (DG) in case BL and the cornu ammonis 1 (CA1) subfield in case BR. BL was impaired in discriminating highly similar objects in memory (i.e., mnemonic discrimination) but exhibited preserved overall recognition of studied objects, regardless of similarity. Conversely, BR demonstrated impaired general recognition. These results provide evidence for the DG in discrimination processes, likely related to underlying pattern separation computations, and the CA1 in retention/retrieval.

Emotional modulation of memorability in mnemonic discrimination.

Although elements such as emotion may serve to enhance or impair memory for images, some images are consistently remembered or forgotten by most people, an intrinsic characteristic of images known as memorability. Memorability explains some of the variability in memory performance, however, the underlying mechanisms of memorability remain unclear. It is known that emotional valence can increase the memorability of an experience, but how these two elements interact is still unknown. Hippocampal pattern separation, a computation that orthogonalizes overlapping experiences as distinct from one another, may be a candidate mechanism underlying memorability. However, these two literatures have remained largely separate. To explore the interaction between image memorability and emotion on pattern separation, we examined performance on an emotional mnemonic discrimination task, a putative behavioral correlate of hippocampal pattern separation, by splitting stimuli into memorable and forgettable categories as determined by a convolutional neural network as well as by emotion, lure similarity, and time of testing (immediately and 24-hour delay). We measured target recognition, which is typically used to determine memorability scores, as well as lure discrimination, which taxes hippocampal pattern separation and has not yet been examined within a memorability framework. Here, we show that more memorable images were better remembered across both target recognition and lure discrimination measures. However, for target recognition, this was only true upon immediate testing, not after a 24-hour delay. For lure discrimination, we found that memorability interacts with lure similarity, but depends on the time of testing, where memorability primarily impacts high similarity lure discrimination when tested immediately but impacts low similarity lure discrimination after a 24-hour delay. Furthermore, only lure discrimination showed an interaction between emotion and memorability, in which forgettable neutral images showed better lure discrimination compared to more memorable images. These results suggest that careful consideration is required of what makes an image memorable and may depend on what aspects of the image are more memorable (e.g., gist vs. detail, emotional vs. neutral).

Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.

Cost-benefit Tradeoff Mediates the Rule- to Memory-based Processing Transition during Practice.

Practice not only improves task performance, but also changes task execution from rule- to memory-based processing by incorporating experiences from practice. However, how and when this change occurs is unclear. We tested the hypothesis that strategy transition in task learning results from cost-benefit analysis. Participants learned two task sequences and were then queried about the task type at a cued sequence and position. Behavioral improvement with practice can be accounted for by a computational model implementing cost-benefit analysis. Model-predicted strategy transition points are related to behavioral slowing and changes in fMRI activation patterns in the dorsolateral prefrontal cortex. Strategy transition is also related to increased pattern separation in the ventromedial prefrontal cortex. The cost-benefit analysis model outperforms alternative models (e.g., both strategies racing for being expressed in behavior) in accounting for empirical data. These findings support cost-benefit analysis as a mechanism of practice-induced strategy shift.

Cross-cultural comparison of the neural correlates of true and false memory retrieval.

Prior work has shown Americans have higher levels of memory specificity than East Asians. Neuroimaging studies have not investigated mechanisms that account for cultural differences at retrieval. In this study, we use fMRI to assess whether mnemonic discrimination, distinguishing novel from previously encountered stimuli, accounts for cultural differences in memory. Fifty-five American and 55 Taiwanese young adults completed an object recognition paradigm testing discrimination of old targets, similar lures and novel foils. Mnemonic discrimination was tested by comparing discrimination of similar lures from studied targets, and results showed the relationship between activity in right fusiform gyrus and behavioural discrimination between target and lure objects differed across cultural groups. Parametric modulation analyses of activity during lure correct rejections also indicated that groups differed in left superior parietal cortex response to variations in lure similarity. Additional analyses of old vs. new activity indicated that Americans and Taiwanese differ in the neural activity supporting general object recognition in the hippocampus, left inferior frontal gyrus and middle frontal gyrus. Results are juxtaposed against comparisons of the regions activated in common across the two cultures. Overall, Americans and Taiwanese differ in the extent to which they recruit visual processing and attention modulating brain regions.

Atypical pattern separation memory and its association with restricted interests and repetitive behaviors in autistic children.

LAY ABSTRACT: Memory challenges remain understudied in childhood autism. Our study investigates one specific aspect of memory function, known as pattern separation memory, in autistic children. Pattern separation memory refers to the critical ability to store unique memories of similar stimuli; however, its role in childhood autism remains largely uncharted. Our study first uncovered that the pattern separation memory was significantly reduced in autistic children, and then showed that reduced memory performance was linked to their symptoms of repetitive, restricted interest and behavior. We also identified distinct subgroups with profiles of reduced and increased generalization for pattern separation memory. More than 72% of autistic children showed a tendency to reduce memory generalization, focusing heavily on unique details of objects for memorization. This focus made it challenging for them to identify commonalities across similar entities. Interestingly, a smaller proportion of autistic children displayed an opposite pattern of increased generalization, marked by challenges in differentiating between similar yet distinct objects. Our findings advance the understanding of memory function in autism and have practical implications for devising personalized learning strategies that align with the unique memory patterns exhibited by autistic children. This study will be of broad interest to researchers in psychology, psychiatry, and brain development as well as teachers, parents, clinicians, and the wider public.