Spatial Pattern Separation Research Articles

The role of the ventral dentate gyrus in olfactory pattern separation

Dorsoventral lesion studies of the hippocampus have indicated that the dorsal axis of the hippocampus is important for spatial processing and the ventral axis of the hippocampus is important for olfactory learning and memory and anxiety. There is some evidence to suggest that the ventral CA3 and ventral CA1 conduct parallel processes for pattern completion and temporal processing, respectively. Studies have indicated that the dorsal dentate gyrus (DG) is importantly involved in processes reflecting underlying pattern separation activity for spatial information. However, the ventral DG is less understood. The current study investigated the less-understood role of the ventral DG in olfactory pattern separation. A series of odor stimuli that varied on only one level, number of carbon chains (methyl groups), was used in a matching-to-sample paradigm in order to investigate ventral DG involvement in working memory for similar and less similar odors. Rats with ventral DG lesions were impaired at delays of 60 sec, but not at delays of 15 sec. A memory-based pattern separation effect was observed performance was poorest with only one carbon chain separation between trial odors and was highest for trials with four separations. The present study indicates that the ventral DG plays an important role in olfactory learning and memory processes for highly similar odors. The results also indicate a role for the ventral DG in pattern separation for odor information, which may have further implications for parallel processing across the dorsoventral axis for the DG in spatial (dorsal) and olfactory (ventral) pattern separation.

Exercise and the brain: a slap on the HAND

Exercise and the brain: a slap on the HAND

Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model.

The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis.

Age-related changes in place learning for adjacent and separate locations

The effect of spatial interference on place learning was examined in young and old rats. Rats were trained on a radial 8-arm maze to discriminate between a reward arm and a nonreward arm that either were adjacent to each other (high spatial interference) or separated by a distance of 2 arm positions (low spatial interference). Each rat was tested until reaching a criterion of 9 correct choices out of 10 trials across 2 consecutive days. The data revealed that old rats committed significantly more errors than young rats when the arms were adjacent and spatial interference was high. However, no group differences were detected when the arms were separated and spatial interference was low. Group differences also were not detected in the number of trials required to reach the learning criterion in either condition. The results indicate that age-related brain changes result in increased errors during place learning, particularly when spatial interference is high, suggesting that spatial pattern separation might be less efficient in aged animals.

Dissociation between memory retention across a delay and pattern separation following medial prefrontal cortex lesions in the touchscreen TUNL task

The neural structures that support the retention of memories over time has been a subject of intense research in cognitive neuroscience. However, recently much attention has turned to pattern separation, the putative process by which memories are stored as unique representations that are resistant to confusion. It remains unclear, however, to what extent these two processes can be neurally dissociated. The trial-unique delayed nonmatching-to-location (TUNL) task was developed to assess spatial working memory and pattern separation function using trial-unique locations on a touch-sensitive screen (Talpos, McTighe, Dias, Saksida, & Bussey, 2010). Using this task, Talpos et al. (2010) showed that lesions of the hippocampus led to both impairments with a 6s delay, and impairments in pattern separation. The present study shows that lesions of the medial prefrontal cortex lead to a different pattern of effects: impairment at the same, 6s delay, but no hint of impairment in pattern separation. In addition, rats with medial prefrontal lesions were more susceptible to interference in this task. When compared with previously published results, these data show that whereas the prefrontal cortex and hippocampus likely interact in the service of working memory across a delay, only the hippocampus and not the medial prefrontal cortex is essential for pattern separation.

A process analysis of the CA3 subregion of the hippocampus

From a behavioral perspective, the CA3a,b subregion of the hippocampus plays an important role in the encoding of new spatial information within short-term memory with a duration of seconds and minutes. This can easily be observed in tasks that require rapid encoding, novelty detection, one-trial short-term or working memory, and one-trial cued recall primarily for spatial information. These are tasks that have been assumed to reflect the operations of episodic memory and require interactions between CA3a,b and the dentate gyrus (DG) via mossy fiber inputs into the CA3a,b. The CA3a,b is also important for encoding of spatial information requiring the acquisition of arbitrary and relational associations. All these tasks are assumed to operate within an autoassociative network function of the CA3 region. The CA3a,b also supports retrieval of short-term memory information based on a spatial pattern completion process. Based on afferent inputs into CA3a,b from the DG via mossy fibers and afferents from the entorhinal cortex into CA3a,b as well as reciprocal connections with the septum, CA3a,b can bias the process of encoding utilizing the operation of spatial pattern separation and the process of retrieval utilizing the operation of pattern completion. The CA3a,b also supports sequential processing of information in cooperation with CA1 based on the Schaffer collateral output from CA3a,b to CA1. The CA3c function is in part based on modulation of the DG in supporting pattern separation processes.

Role of the hippocampus in mediating interference as measured by pattern separation processes

In order to understand the neural mechanism associated with specific forms of interference, this manuscript concentrates on the role of the dorsal and ventral dentate gyrus subregions of the hippocampus in rats. The computational modelers have suggested that the dentate gyrus can provide a neural mechanism that can operate to reduce interference between highly processed similar spatial, contextual or odor inputs to generate pattern separation functions. Pattern separation which is defined as a process to remove redundancy from similar inputs so that events can be separated from each other and interference can be reduced, and in addition can produce a more orthogonal, sparse, and categorized set of outputs. It appears that the anatomical organization of the hippocampus may provide the answer for the importance of interference in mnemonic processing of information. Therefore, in the first part of this paper an anatomical description of the inputs and outputs of the hippocampus as well as its intrinsic circuit is provided. This is followed by the presentation of data to support the role of the dorsal DG in supporting spatial pattern separation, dorsal CA1 in supporting temporal pattern separation for spatial locations and visual objects, ventral DG in supporting odor pattern separation, and ventral CA1 in supporting temporal pattern separation for odors.

CGG trinucleotide repeat length modulates neural plasticity and spatiotemporal processing in a mouse model of the fragile X premutation

The fragile X premutation is a CGG repeat expansion on the FMR1 gene between 55 and 200 repeats in length. It has been proposed that impaired spatiotemporal function underlies cognitive deficits in genetic disorders, including the fragile X premutation. This study characterized the role of the premutation for cognitive function by demonstrating CGG KI mice with 70-198 CGG repeats show deficits across tasks requiring spatial and temporal pattern separation. To elucidate mechanisms whereby CGG repeats affect spatiotemporal processing, hippocampal slices were evaluated for LTP, LTD, and mGluR1/5 LTD. Increasing CGG repeat length modulated the induction of LTP, LTD, and mGluR1/5 LTD, as well as behavioral tasks emphasizing spatiotemporal processing. Despite the deficits in the induction of all forms of plasticity, there were no differences in expression of plasticity once evoked. These data provide evidence for a neurocognitive endophenotype in the CGG KI mouse model of the premutation in which CGG repeat length negatively modulates plasticity and spatiotemporal attention.

SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis‐dependent learning and memory

SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients.

Differential roles of the dorsal hippocampal regions in the acquisition of spatial and temporal aspects of episodic-like memory

Episodic memory refers to the recollection of what, where and when an event occurred. Computational models suggest that the dentate gyrus (DG) and the CA3 hippocampal subregions are involved in pattern separation and the rapid acquisition of episodes, while CA1 is involved in the formation of a temporal context. Most of the studies performed to test this hypothesis failed to simultaneously address the aspects of episodic memory. Recently, a new task of object recognition was validated in rats. In the first sample trial, the rat is exposed to four copies of an object. In second sample, the rat is exposed to four copies of a different object. In the test trial, two copies of each of the previous objects are presented. One copy of the object used in sample trial one is located in a different place, and it is expected to be the most explored. Our goal was to evaluate whether the pharmacological inactivation of the dorsal DG/CA3 and CA1 subregions could differentially impair the acquisition of the task. Inactivation of the DG/CA3 subregions impaired the spatial discrimination, while the temporal discrimination was preserved. Rats treated with muscimol in CA1 explored all the objects equally well, irrespective of place or presentation time. Our results are consistent with computational models that postulate a role for DG/CA3 in rapid encoding and in spatial pattern separation, and a role for CA1 in the in the formation of the temporal context of events and as well as in detecting spatial novelty.

Spatial pattern separation in cognitively normal young and older adults

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.

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

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.

Less efficient pattern separation may contribute to age-related spatial memory deficits

Spatial memory deficits have been well-documented in older adults and may serve as an early indicator of mild cognitive impairment (MCI) or Alzheimer's disease (AD) in some individuals. Pattern separation is a critical mechanism for reducing potential interference among similar memory representations to enhance memory accuracy. A small but growing literature indicates that spatial pattern separation may become less efficient as a result of normal aging, possibly due to age-related changes in subregions of the hippocampus. This decreased efficiency in spatial pattern separation may be a critical processing deficit that could be a contributing factor to spatial memory deficits and episodic memory impairment associated with aging. The present paper will review recently published studies in humans, non-human primates, and rodents that have examined age-related changes in spatial pattern separation. The potential basic science, translational, and clinical implications from these studies are discussed to illustrate the need for future research to further examine the relationship between spatial pattern separation and brain changes associated with aging and neurodegenerative disease.

CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement

The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB-binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.

Virtual human analogs to rodent spatial pattern separation and completion memory tasks

Spatial pattern separation (SPS) and spatial pattern completion (SPC) have played an increasingly important role in computational and rodent literatures as processes underlying associative memory. SPS and SPC are complementary processes, allowing the formation of unique representations and the reconstruction of complete spatial environments based on partial spatial information. We present two novel computerized navigational tasks as human analogs of well-established rat SPS and SPC tasks. Results from these tasks show that human participants are sensitive to increasing SPS and SPC demands. Specifically, memory accuracy decreased with decreasing separation distance between target and foil locations in the SPS task and with decreasing number of distal spatial cues in the SPC task. These tasks set the stage for valuable future directions, including the use of these tasks with imaging and clinical populations.

Adult‐born neurons are necessary for extended contextual discrimination

New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.

Trial-unique, delayed nonmatching-to-location (TUNL): A novel, highly hippocampus-dependent automated touchscreen test of location memory and pattern separation

The hippocampus is known to be important for learning and memory, and is implicated in many neurodegenerative diseases. Accordingly many animal models of learning and memory focus on hippocampus-dependent tests of location learning and memory. These tests often use dry mazes or water mazes; however automated testing in operant chambers confers many advantages over such methods. Some automated tests of location memory, such as delayed nonmatching-to-position (DNMTP) have, however, fallen out of favor following the discovery that such tasks can be solved using mediating behaviors that can bridge the delay and reduce the requirement for memory per se. Furthermore some researchers report that DNMTP performance may not always require the hippocampus. Thus, in an attempt to develop a highly hippocampus-dependent automated test of location memory that elicits fewer mediating behaviors, we have developed a trial-unique nonmatching-to-location (TUNL) task, carried out in a computer-automated touchscreen testing apparatus. To test the efficacy of this assay, rats with lesions to the hippocampus, or a sham lesion control group, were tested under a variety of conditions. Both groups were able to perform well at a delay of 1s, but the lesion group was highly impaired when tested at a 6s delay. Moreover, animals with lesions of the hippocampus showed a greater impairment when the distance between the locations was reduced. This result indicates that TUNL can be used to investigate both memory across a delay, and spatial pattern separation (the ability to disambiguate similar spatial locations). Performance-enhancing mediating behaviors during the task were found to be minimal. Thus, the TUNL task has the potential to serve as a powerful tool for the study of the neurobiology of learning and memory.

Variability in Spatial Pattern Separation Performance in Memory Impaired and Unimpaired Older Adults

Variability in Spatial Pattern Separation Performance in Memory Impaired and Unimpaired Older Adults

Individual differences in spatial pattern separation performance associated with healthy aging in humans

Rodent studies have suggested that "pattern separation," the ability to distinguish among similar experiences, is diminished in a subset of aged rats. We extended these findings to the human using a task designed to assess spatial pattern separation behavior (determining at time of test whether pairs of pictures shown during the study were in the same spatial locations). Using a standardized test of word recall to divide healthy aged adults into impaired and unimpaired groups relative to young performance, we demonstrate that aged impaired adults are biased away from pattern separation and toward pattern completion, consistent with the rodent studies.

Running enhances spatial pattern separation in mice

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.