The role of the dorsal CA3 hippocampal subregion in spatial working memory and pattern separation

This study presents a double dissociation between the dentate gyrus (DG) and CA1. Rats with either DG or CA1 lesions were tested on tasks requiring either spatial or spatial temporal order pattern separation. To assess spatial pattern separation, rats were trained to displace an object which covered a baited food-well. The rats were then allowed to choose between two identical objects: one covered the same well as the sample phase object (correct choice), and a second object covered a different unbaited well (incorrect choice). Spatial separations of 15-105 cm were used to separate the correct object from the incorrect object. To assess spatial temporal order pattern separation, rats were allowed to visit each arm of a radial eight-arm maze once in a randomly determined sequence. The rats were then presented with two arms and were required to choose the arm which occurred earliest in the sequence. The choice arms varied according to temporal separation (0, 2, 4, or 6) or the number of arms that occurred between the two choice arms in the sample phase sequence. On each task, once a preoperative criterion was reached, each rat was given either a DG, CA1, or control lesion and then retested. The results demonstrated that DG lesions resulted in a deficit on the spatial task but not the temporal task. In contrast, CA1 lesions resulted in a deficit on the temporal task but not the spatial task. Results suggest that the DG supports spatial pattern separation, whereas CA1 supports temporal pattern separation.

A paradigm based on measuring short-term memory for spatial location information as a function of spatial similarity between distal cues was developed to examine the role of pattern separation in the modulation of short-term memory for spatial information. A delayed-match-to-sample for spatial location task using a dryland version of the Morris water maze was used to assess spatial pattern separation in male Long-Evans rats. In the sample phase, animals were trained to displace an object that covered a baited food well in one of 15 spatial locations along a row of food wells perpendicular to a start box. In the ensuing choice phase, the animal was allowed to choose between two objects identical to the sample phase object. One covered the same baited food well as did the object in the study phase (correct choice), and another foil object (incorrect choice) covered a different unbaited food well along the row of wells. Five spatial separations were randomly used to separate the correct object from the foil object. After reaching a criterion before the operation, animals were given either hippocampal or cortical control lesions. In trials after the operation, control animals matched their performance before the operation across all spatial separations. In contrast, hippocampal-lesioned animals displayed impairments across all spatial separations with the exception of the longest (105 cm) spatial separation. The results suggest that the hippocampus may serve to separate incoming spatial information by temporarily storing one place separate from another. It is proposed that hippocampal lesions decrease efficiency in pattern separation, resulting in impairments in trials with increased spatial similarity among working-memory representations.

Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations

The role of the CA3 hippocampal subregion in spatial memory: A process oriented behavioral assessment

The newly discovered brain-specific transmembrane protein CKAMP44 was shown to influence AMPA receptor function in the mouse hippocampus where the protein is differentially expressed. The low mRNA expression in CA1-neurons versus the high expression in DGneurons gives reason to hypothesize that the different CKAMP44 levels influence memory processes assigned to these subfields. The DG has long been proposed to provide the cellular substrate for the process of spatial pattern separation, whereas CA1 is assumed to be the basis of temporal pattern separation. To investigate these hypotheses, two mouse models of altered CKAMP44 expression were analyzed. Theoretically, a global knockout of CKAMP44 should influence a region with high endogenous CKAMP44 expression (DG) more than a region with low expression (CA1). Vice versa, CKAMP44 overexpression should exert a stronger influence on a region with low (CA1) than on a region with high expression (DG). Thus, the CKAMP44-/- mice served as a model to study the involvement of CKAMP44 in the DG-based spatial pattern separation. CKAMP44-/- mice failed to show any impairment in hippocampus-dependent spatial reference- and spatial working-memory tests including spatial pattern separation. In the second model, virusmediated CKAMP44 overexpression was confined to the hippocampus. Compared to Controls, CKAMP44HCoex mice made a similar number of errors during both spatial reference- and spatial working-memory test on the eight-arm radial arm maze. But a newly designed analysis of the working memory errors on the eight-arm radial arm maze and the chance-level performance during rewarded alternation revealed an impairment in the ability to process or retrieve stimulusspecific, recency-dependent memory in CKAMP44HCoex mice. Thus, the CKAMP44HCoex model adds further proof to the implicated role for CA1 in temporal pattern separation, and also provides the hitherto only model of altered hippocampal memory funciton upon manipulation of an AMPA receptor auxiliary protein.

Enhancing spatial memory and pattern separation: Long-term effects of stimulant treatment in individuals with ADHD

Enhancement of Learning and Memory by Elevating Brain Magnesium

This study examined the ability of cognitively normal young adults (n = 30) and older adults (n = 30) to perform a delayed match-to-sample task involving varying degrees of spatial interference to assess spatial pattern separation. Each trial consisted of a sample phase followed by a choice phase. During the sample phase, a circle appeared briefly on a computer screen. The participant was instructed to remember the location of the circle on the screen. During the choice phase, two circles were displayed simultaneously, and the participant was asked to indicate which circle was in the same location as the sample phase circle. The two circles on choice phase trials were separated by one of four possible spatial separations: 0, 0.5, 1.0, and 1.5 cm. Smaller separations are likely to create increased overlap among memory representations, which may result in heightened interference and a greater need for pattern separation. Consistent with this hypothesis, performance increased as a function of increased spatial separation in both young and older adults. However, young adults outperformed older adults, suggesting that spatial pattern separation may be less efficient in older adults due to potential age-related changes in the dentate gyrus and CA3 hippocampal subregions. Older adults also were divided into older impaired and older unimpaired groups based on their performance on a standardized test of verbal memory. The older impaired group was significantly impaired relative to both the older unimpaired and young groups, suggesting that pattern separation deficits may be variable in older adults. The present findings may have important implications for designing behavioral interventions for older adults that structure daily living tasks to reduce interference, thus improving memory function.

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.

Working memory is a fundamental cognitive process for decision-making and is a hallmark impairment in a variety of neuropsychiatric and neurodegenerative diseases. Spatial working memory paradigms are a valuable tool to assess these processes in rodents and dissect the neurobiology underlying working memory. The trial unique non-match to location (TUNL) task is an automated touchscreen paradigm used to study spatial working memory and pattern separation processes in rodents. Here, animals must remember the spatial location of a stimulus presented on the screen over a delay period; and use this representation to respond to the novel location when the two are presented together. Because stimuli can be presented in a variety of spatial configurations, TUNL offers a trial-unique paradigm, which can aid in combating the development of unwanted mediating strategies. Here, we have optimized the TUNL protocol for mice to reduce training time and further reduce the potential development of mediating strategies. As a result, mice are able to accurately perform an enhanced trial-unique paradigm, where the locations of the sample and choice stimuli can be presented in any configuration on the screen during a single session. We also aimed to pharmacologically characterize this updated protocol, by assessing the roles of the medial prefrontal cortex (mPFC) and N-methyl-D-aspartate (NMDA) receptor (NMDAr) functioning during TUNL. Temporary inactivation of the medial prefrontal cortex (mPFC) was accomplished by directly infusing a mixture of GABA agonists muscimol and baclofen into the mPFC. We found that mPFC inactivation significantly impaired TUNL performance in a delay-dependent manner. In addition, mPFC inactivation significantly increased the susceptibility of mice to proactive interference. Mice were then challenged with acute systemic injections of the NMDAr antagonist ketamine, which resulted in a dose-dependent, delay-dependent working memory impairment. Together, we describe an optimized automated touchscreen task of working memory, which is dependent on the intact functioning of the mPFC and sensitive to acute NMDAr hypofunction. With the vast genetic toolbox available for modeling disease and probing neural circuit functioning in mice, the TUNL task offers a valuable paradigm to pair with these technologies to further investigate the processes underlying spatial working memory.

P192 Investigating the role of the parietal and prefrontal cortices in spatial working memory using transcranial direct current stimulation

This study examined how spatial working memory and visual (object) working memory interact, focusing on two related questions: First, can these systems function independently from one another? Second, under what conditions do they operate together? In a dual-task paradigm, participants attempted to remember locations in a spatial working memory task and colored objects in a visual working memory task. Memory for the locations and objects was subject to independent working memory storage limits, which indicates that spatial and visual working memory can function independently from one another. However, additional experiments revealed that spatial working memory and visual working memory interact in three memory contexts: when retaining (1) shapes, (2) integrated color-shape objects, and (3) colored objects at specific locations. These results suggest that spatial working memory is needed to bind colors and shapes into integrated object representations in visual working memory. Further, this study reveals a set of conditions in which spatial and visual working memory can be isolated from one another.

Anxiety can be distracting, disruptive, and incapacitating. Despite problems with empirical replication of this phenomenon, one fruitful avenue of study has emerged from working memory (WM) experiments where a translational method of anxiety induction (risk of shock) has been shown to disrupt spatial and verbal WM performance. Performance declines when resources (e.g., spatial attention, executive function) devoted to goal-directed behaviors are consumed by anxiety. Importantly, it has been shown that anxiety-related impairments in verbal WM depend on task difficulty, suggesting that cognitive load may be an important consideration in the interaction between anxiety and cognition. Here we use both spatial and verbal WM paradigms to probe the effect of cognitive load on anxiety-induced WM impairment across task modality. Subjects performed a series of spatial and verbal n-back tasks of increasing difficulty (1, 2, and 3-back) while they were safe or at risk for shock. Startle reflex was used to probe anxiety. Results demonstrate that induced-anxiety differentially impacts verbal and spatial WM, such that low and medium-load verbal WM is more susceptible to anxiety-related disruption relative to high-load, and spatial WM is disrupted regardless of task difficulty. Anxiety impacts both verbal and spatial processes, as described by correlations between anxiety and performance impairment, albeit the effect on spatial WM is consistent across load. Demanding WM tasks may exert top-down control over higher-order cortical resources engaged by anxious apprehension, however high-load spatial WM may continue to experience additional competition from anxiety-related changes in spatial attention, resulting in impaired performance. By describing this disruption across task modalities, these findings inform current theories of emotion–cognition interactions and may facilitate development of clinical interventions that seek to target cognitive impairments associated with anxiety.

Acute sleep loss impairs object but not spatial pattern separation in humans

The hippocampus, entorhinal cortex, and basal forebrain are among the first brain structures affected by Alzheimer's disease (AD). They play an essential role in spatial pattern separation, a process critical for accurate encoding of similar spatial information. Our aim was to examine spatial pattern separation and its association with volumetric changes of the hippocampus, entorhinal cortex, and basal forebrain nuclei projecting to the hippocampus (the medial septal nuclei and vertical limb of the diagonal band of Broca - Ch1-2 nuclei) in the biomarker-defined early clinical stages of AD. A total of 98 older adults were recruited from the Czech Brain Aging Study cohort. The participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 44), mild AD dementia (n = 31), and cognitively normal older adults (CN; n = 23) underwent spatial pattern separation testing, comprehensive cognitive assessment, and MRI brain volumetry. Spatial pattern separation accuracy was lower in the early clinical stages of AD compared to the CN group (p < 0.001) and decreased with disease severity (CN > aMCI due to AD > AD dementia). Controlling for general memory and cognitive performance, demographic characteristics and psychological factors did not change the results. Hippocampal and Ch1-2 volumes were directly associated with spatial pattern separation performance while the entorhinal cortex operated on pattern separation indirectly through the hippocampus. Smaller volumes of the hippocampus, entorhinal cortex, and basal forebrain Ch1-2 nuclei are linked to spatial pattern separation impairment in biomarker-defined early clinical AD and may contribute to AD-related spatial memory deficits.