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Hippocampal place cells are influenced by both self-motion (idiothetic) signals and external sensory landmarks as an animal navigates its environment. To continuously update a position signal on an internal 'cognitive map', the hippocampal system integrates self-motion signals over time, a process that relies on a finely calibrated path integration gain that relates movement in physical space to movement on the cognitive map. It is unclear whether idiothetic cues alone, such as optic flow, exert sufficient influence on the cognitive map to enable recalibration of path integration, or if polarizing position information provided by landmarks is essential for this recalibration. Here, we demonstrate both recalibration of path integration gain and systematic control of place fields by pure optic flow information in freely moving rats. These findings demonstrate that the brain continuously rebalances the influence of conflicting idiothetic cues to fine-tune the neural dynamics of path integration, and that this recalibration process does not require a top-down, unambiguous position signal from landmarks., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases. In the Morris water maze, aged memory-unimpaired (AU) rats navigate to remembered goal locations as effectively as young rats and demonstrate minimal alterations in physiological markers of synaptic plasticity, whereas aged memory-impaired (AI) rats show impairments in both spatial navigation skills and cellular and molecular markers of plasticity. The present study investigates whether another cognitive domain is affected similarly to navigation in aged Long-Evans rats. We tested the ability of young, AU, and AI animals to recognize novel object-place-context (OPC) configurations and found that performance on the novel OPC recognition paradigm was significantly correlated with performance on the Morris water maze. In the first OPC test, young and AU rats, but not AI rats, successfully recognized and preferentially explored objects in novel OPC configurations. In a second test with new OPC configurations, all age groups showed similar OPC associative recognition memory. The results demonstrated similarities in the behavioral expression of associative, episodic-like memory between young and AU rats and revealed age-related, individual differences in functional decline in both navigation and episodic-like memory abilities., (© 2023 Wiley Periodicals LLC.)

There has been considerable speculation regarding the function of the dentate gyrus (DG) - a subregion of the mammalian hippocampus - in learning and memory. In this Perspective article, we compare leading theories of DG function. We note that these theories all critically rely on the generation of distinct patterns of activity in the region to signal differences between experiences and to reduce interference between memories. However, these theories are divided by the roles they attribute to the DG during learning and recall and by the contributions they ascribe to specific inputs or cell types within the DG. These differences influence the information that the DG is thought to impart to downstream structures. We work towards a holistic view of the role of DG in learning and memory by first developing three critical questions to foster a dialogue between the leading theories. We then evaluate the extent to which previous studies address our questions, highlight remaining areas of conflict, and suggest future experiments to bridge these theories., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Entorhinal cortex is the major gateway between the neocortex and the hippocampus and thus plays an essential role in subserving episodic memory and spatial navigation. It can be divided into the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), which are commonly theorized to be critical for spatial (context) and non-spatial (content) inputs, respectively. Consistent with this theory, LEC neurons are found to carry little information about allocentric self-location, even in cue-rich environments, but they exhibit egocentric spatial information about external items in the environment. The superficial and deep layers of LEC are believed to mediate the input to and output from the hippocampus, respectively. As earlier studies mainly examined the spatial firing properties of superficial-layer LEC neurons, here we characterized the deep-layer LEC neurons and made direct comparisons with their superficial counterparts in single unit recordings from behaving rats. Because deep-layer LEC cells received inputs from hippocampal regions, which have strong selectivity for self-location, we hypothesized that deep-layer LEC neurons would be more informative about allocentric position than superficial-layer LEC neurons. We found that deep-layer LEC cells showed only slightly more allocentric spatial information and higher spatial consistency than superficial-layer LEC cells. Egocentric coding properties were comparable between these two subregions. In addition, LEC neurons demonstrated preferential firing at lower speeds, as well as at the boundary or corners of the environment. These results suggest that allocentric spatial outputs from the hippocampus are transformed in deep-layer LEC into the egocentric coding dimensions of LEC, rather than maintaining the allocentric spatial tuning of the CA1 place fields., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. Functional heterogeneity in CA3 was observed in Y and AU rats when the environmental similarity was high (altered cues or altered environment shapes in the same room), with more orthogonalized representations in proximal CA3 than in distal CA3. In contrast, AI rats showed reduced orthogonalization in proximal CA3 but showed normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. Under experimental conditions when the environmental similarity was low (different rooms), representations in proximal and distal CA3 remapped in all rats, showing that CA3 of AI rats is able to encode distinctive representations for inputs with greater dissimilarity. These experiments support the hypotheses that the age-related bias toward hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis., Competing Interests: Declaration of interests M.G. is the founder of AgeneBio Incorporated, a biotechnology company that is dedicated to discovery and development of therapies to treat cognitive impairment. M.G. has a financial interest in the company and is an inventor on Johns Hopkins University’s intellectual property that is licensed to AgeneBio. Otherwise, M.G. has had no consulting relationship with other public or private entities in the past 3 years and has no other financial holdings that could be perceived as constituting a potential conflict of interest. All conflicts of interest are managed by Johns Hopkins University. All other authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The hippocampus is involved in the formation of memories that require associations among stimuli to construct representations of space and the items and events within that space. Neurons in the dentate gyrus (DG), an initial input region of the hippocampus, have robust spatial tuning, but it is unclear how nonspatial information may be integrated with spatial activity in this region. We recorded from the DG of 21 adult mice as they foraged for food in an environment that contained discrete objects. We found DG cells with multiple firing fields at a fixed distance and direction from objects (landmark vector cells) and cells that exhibited localized changes in spatial firing when objects in the environment were manipulated. By classifying recorded DG cells into putative dentate granule cells and mossy cells, we examined how the addition or displacement of objects affected the spatial firing of these DG cell types. Object-related activity was detected in a significant proportion of mossy cells. Although few granule cells with responses to object manipulations were recorded, likely because of the sparse nature of granule cell firing, there was generally no significant difference in the proportion of granule cells and mossy cells with object responses. When mice explored a second environment with the same objects, DG spatial maps completely reorganized, and a different subset of cells responded to object manipulations. Together, these data reveal the capacity of DG cells to detect small changes in the environment while preserving a stable spatial representation of the overall context., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Camera images can encode large amounts of visual information of an animal and its environment, enabling high fidelity 3D reconstruction of the animal and its environment using computer vision methods. Most systems, both markerless (e.g. deep learning based) and marker-based, require multiple cameras to track features across multiple points of view to enable such 3D reconstruction. However, such systems can be expensive and are challenging to set up in small animal research apparatuses., New Methods: We present an open-source, marker-based system for tracking the head of a rodent for behavioral research that requires only a single camera with a potentially wide field of view. The system features a lightweight visual target and computer vision algorithms that together enable high-accuracy tracking of the six-degree-of-freedom position and orientation of the animal's head. The system, which only requires a single camera positioned above the behavioral arena, robustly reconstructs the pose over a wide range of head angles (360° in yaw, and approximately ± 120° in roll and pitch)., Results: Experiments with live animals demonstrate that the system can reliably identify rat head position and orientation. Evaluations using a commercial optical tracker device show that the system achieves accuracy that rivals commercial multi-camera systems., Comparison With Existing Methods: Our solution significantly improves upon existing monocular marker-based tracking methods, both in accuracy and in allowable range of motion., Conclusions: The proposed system enables the study of complex behaviors by providing robust, fine-scale measurements of rodent head motions in a wide range of orientations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The cognitive map in the hippocampal formation of rodents and other mammals integrates multiple classes of sensory and motor information into a coherent representation of space. Here, we describe the Dome, a virtual reality apparatus for freely locomoting rats, designed to examine the relative contributions of various spatial inputs to an animal's spatial representation. The Dome was designed to preserve the range of spatial inputs typically available to an animal in free, untethered locomotion while providing the ability to perturb specific sensory cues. We present the design rationale and corresponding specifications of the Dome, along with a variety of engineering and biological analyses to validate the efficacy of the Dome as an experimental tool to examine the interaction between visual information and path integration in place cells in rodents., (Copyright © 2021. Published by Elsevier B.V.)

"Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the aged-impaired rats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions. SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3., (Copyright © 2021 the authors.)

The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories. Classic computational models have suggested that the dentate gyrus (DG) supports pattern separation and the putative attractor circuitry in CA3 supports pattern completion. However, recent evidence of functional heterogeneity along the CA3 transverse axis of the hippocampus suggests that the DG and proximal CA3 work as a functional unit for pattern separation, while distal CA3 forms an autoassociative network for pattern completion. We propose that the outputs of these functional circuits, combined with direct projections from entorhinal cortex to CA1, form interconnected, parallel processing circuits to support accurate memory storage and retrieval., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The cognitive map is often assumed to be a Euclidean map that isometrically represents the real world (i.e., the Euclidean distance between any two locations in the physical world should be preserved on the cognitive map). However, accumulating evidence suggests that environmental boundaries can distort the mental representations of physical space. For example, the distance between two locations can be remembered as longer than the true physical distance if the locations are separated by a boundary. While this overestimation is observed under different experimental conditions, even when the boundary is formed by flat surface cues, its physiological basis is not well understood. We examined the neural representation of flat surface cue boundaries, and of the space segregated by these boundaries, by recording place cell activity from CA1 and CA3 while rats foraged on a circular track or square platforms with inhomogeneous surface textures. About 40% of the place field edges concentrated near the boundaries on the circular track (significantly above the chance level 33%). Similarly, place field edges were more prevalent near boundaries on the platforms than expected by chance. In both one- and two-dimensional environments, the population vectors of place cell activity changed more abruptly with distance between locations that crossed cue boundaries than between locations within a bounded region. These results show that the locations of surface boundaries were evident as enhanced decorrelations of the neural representations of locations to either side of the boundaries. This enhancement might underlie the cognitive phenomenon of overestimation of distances across boundaries., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Spatial signals are prevalent within the hippocampus and its neighboring regions. It is generally accepted that these signals are defined with respect to the external world (i.e., a world-centered, or allocentric, frame of reference). Recently, evidence of egocentric processing (i.e., self-centered, defined relative to the subject) in the extended hippocampal system has accumulated. These results support the idea that egocentric sensory information, derived from primary sensory cortical areas, may be transformed to allocentric representations that interact with the allocentric hippocampal system. We propose a framework to explain the implications of the egocentric-allocentric transformations to the functions of the medial temporal lobe memory system., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and proximal CA3 (pCA3) regions have been implicated in pattern separation, in part through extracellular recording studies of these areas. However, the DG contains two types of excitatory cells: granule cells of the granule layer and mossy cells of the hilus. Little is known about the firing properties of mossy cells in freely moving animals, and it is unclear how their activity may contribute to the mnemonic functions of the hippocampus. Furthermore, tetrodes in the dentate granule layer and pCA3 pyramidal layer can also record mossy cells, thus introducing ambiguity into the identification of cell types recorded. Using a random forests classifier, we classified cells recorded in DG (Neunuebel and Knierim, 2014) and pCA3 (Lee et al., 2015) of 16 male rats and separately examined the responses of granule cells, mossy cells, and pCA3 pyramidal cells in a local/global cue mismatch task. All three cell types displayed low correlations between the population representations of the rat's position in the standard and cue-mismatch sessions. These results suggest that all three excitatory cell types within the DG/pCA3 circuit may act as a single functional unit to support pattern separation. SIGNIFICANCE STATEMENT Mossy cells in the dentate gyrus (DG) are an integral component of the DG/pCA3 circuit. While the role of granule cells in the circuitry and computations of the hippocampus has been a focus of study for decades, the contributions of mossy cells have been largely overlooked. Recent studies have revealed the spatial firing properties of mossy cells in awake behaving animals, but how the activity of these highly active cells contributes to the mnemonic functions of the DG is uncertain. We separately analyzed mossy cells, granule cells, and pCA3 cells and found that all three cell types respond similarly to a local/global cue mismatch, suggesting that they form a single functional unit supporting pattern separation., (Copyright © 2019 the authors.)

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory. Although behavioral measures and hippocampal gene induction associated with neural activity and synaptic plasticity were similar across age groups, a marker for inhibitory interneuron function in the hippocampal formation was distinctively increased only in aged rats but not in young adults. Because heightened hippocampal neural activity is associated with age-related memory impairment across species, including rats, monkeys, and humans, this finding may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Path integration is a straightforward concept with varied connotations that are important to different disciplines concerned with navigation, such as ethology, cognitive science, robotics and neuroscience. In studying the hippocampal formation, it is fruitful to think of path integration as a computation that transforms a sense of motion into a sense of location, continuously integrated with landmark perception. Here, we review experimental evidence that path integration is intimately involved in fundamental properties of place cells and other spatial cells that are thought to support a cognitive abstraction of space in this brain system. We discuss hypotheses about the anatomical and computational origin of path integration in the well-characterized circuits of the rodent limbic system. We highlight how computational frameworks for map-building in robotics and cognitive science alike suggest an essential role for path integration in the creation of a new map in unfamiliar territory, and how this very role can help us make sense of differences in neurophysiological data from novel versus familiar and small versus large environments. Similar computational principles could be at work when the hippocampus builds certain non-spatial representations, such as time intervals or trajectories defined in a sensory stimulus space., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Hippocampal place cells are spatially tuned neurons that serve as elements of a 'cognitive map' in the mammalian brain 1 . To detect the animal's location, place cells are thought to rely upon two interacting mechanisms: sensing the position of the animal relative to familiar landmarks 2,3 and measuring the distance and direction that the animal has travelled from previously occupied locations 4-7 . The latter mechanism-known as path integration-requires a finely tuned gain factor that relates the animal's self-movement to the updating of position on the internal cognitive map, as well as external landmarks to correct the positional error that accumulates 8,9 . Models of hippocampal place cells and entorhinal grid cells based on path integration treat the path-integration gain as a constant 9-14 , but behavioural evidence in humans suggests that the gain is modifiable 15 . Here we show, using physiological evidence from rat hippocampal place cells, that the path-integration gain is a highly plastic variable that can be altered by persistent conflict between self-motion cues and feedback from external landmarks. In an augmented-reality system, visual landmarks were moved in proportion to the movement of a rat on a circular track, creating continuous conflict with path integration. Sustained exposure to this cue conflict resulted in predictable and prolonged recalibration of the path-integration gain, as estimated from the place cells after the landmarks were turned off. We propose that this rapid plasticity keeps the positional update in register with the movement of the rat in the external world over behavioural timescales. These results also demonstrate that visual landmarks not only provide a signal to correct cumulative error in the path-integration system 4,8,16-19 , but also rapidly fine-tune the integration computation itself.

Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The encoding of time and its binding to events are crucial for episodic memory, but how these processes are carried out in hippocampal-entorhinal circuits is unclear. Here we show in freely foraging rats that temporal information is robustly encoded across time scales from seconds to hours within the overall population state of the lateral entorhinal cortex. Similarly pronounced encoding of time was not present in the medial entorhinal cortex or in hippocampal areas CA3-CA1. When animals' experiences were constrained by behavioural tasks to become similar across repeated trials, the encoding of temporal flow across trials was reduced, whereas the encoding of time relative to the start of trials was improved. The findings suggest that populations of lateral entorhinal cortex neurons represent time inherently through the encoding of experience. This representation of episodic time may be integrated with spatial inputs from the medial entorhinal cortex in the hippocampus, allowing the hippocampus to store a unified representation of what, where and when.

The dentate gyrus (DG) is hypothesized to be a pattern separator crucial for distinguishing similar memories. In this issue of Neuron, a new study by van Dijk and Fenton (2018) revealed that transient changes of firing patterns of DG ensembles, but not the remapping of session-averaged place fields, contributed to a place discrimination task., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Distinct processing of objects and space has been an organizing principle for studying higher-level vision and medial temporal lobe memory. Here, however, we discuss how object and spatial information are in fact closely integrated in vision and memory. The ventral, object-processing visual pathway carries precise spatial information, transformed from retinotopic coordinates into relative dimensions. At the final stages of the ventral pathway, including the dorsal anterior temporal lobe (TEd), object-sensitive neurons are intermixed with neurons that process large-scale environmental space. TEd projects primarily to perirhinal cortex (PRC), which in turn projects to lateral entorhinal cortex (LEC). PRC and LEC also combine object and spatial information. For example, PRC and LEC neurons exhibit place fields that are evoked by landmark objects or the remembered locations of objects. Thus, spatial information, on both local and global scales, is deeply integrated into the ventral (temporal) object-processing pathway in vision and memory.

Granule cells in the dentate gyrus of the hippocampus are thought to be essential to memory function by decorrelating overlapping input patterns (pattern separation). A second excitatory cell type in the dentate gyrus, the mossy cell, forms an intricate circuit with granule cells, CA3c pyramidal cells, and local interneurons, but the influence of mossy cells on dentate function is often overlooked. Multiple tetrode recordings, supported by juxtacellular recording techniques, showed that granule cells fired very sparsely, whereas mossy cells in the hilus fired promiscuously in multiple locations and in multiple environments. The activity patterns of these cell types thus represent different environments through distinct computational mechanisms: sparse coding in granule cells and changes in firing field locations in mossy cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Grid cells represent an ideal candidate to investigate the allocentric determinants of the brain's cognitive map. Most studies of grid cells emphasized the roles of geometric boundaries within the navigational range of the animal. Behaviors such as novel route-taking between local environments indicate the presence of additional inputs from remote cues beyond the navigational borders. To investigate these influences, we recorded grid cells as rats explored an open-field platform in a room with salient, remote cues. The platform was rotated or translated relative to the room frame of reference. Although the local, geometric frame of reference often exerted the strongest control over the grids, the remote cues demonstrated a consistent, sometimes dominant, countervailing influence. Thus, grid cells are controlled by both local geometric boundaries and remote spatial cues, consistent with prior studies of hippocampal place cells and providing a rich representational repertoire to support complex navigational (and perhaps mnemonic) processes., Competing Interests: The authors declare that no competing interests exist.

Classic computational theories of the mnemonic functions of the hippocampus ascribe the processes of pattern separation to the dentate gyrus (DG) and pattern completion to the CA3 region. Until the last decade, the large majority of single-unit studies of the hippocampus in behaving animals were from the CA1 region. The lack of data from the DG, CA3, and the entorhinal inputs to the hippocampus severely hampered the ability to test these theories with neurophysiological techniques. The past ten years have seen a major increase in the recordings from the CA3 region and the medial entorhinal cortex (MEC), with an increasing (but still limited) number of experiments from the lateral entorhinal cortex (LEC) and DG. This paper reviews a series of studies in a local-global cue mismatch (double-rotation) experiment in which recordings were made from cells in the anterior thalamus, MEC, LEC, DG, CA3, and CA1 regions. Compared to the standard cue environment, the change in the DG representation of the cue-mismatch environment was greater than the changes in its entorhinal inputs, providing support for the theory of pattern separation in the DG. In contrast, the change in the CA3 representation of the cue-mismatch environment was less than the changes in its entorhinal and DG inputs, providing support for a pattern completion/error correction function of CA3. The results are interpreted in terms of continuous attractor network models of the hippocampus and the relationship of these models to pattern separation and pattern completion theories. Whereas DG may perform an automatic pattern separation function, the attractor dynamics of CA3 allow it to perform a pattern separation or pattern completion function, depending on the nature of its inputs and the relative strength of the internal attractor dynamics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Classical theories of associative memory model CA3 as a homogeneous attractor network because of its strong recurrent circuitry. However, anatomical gradients suggest a functional diversity along the CA3 transverse axis. We examined the neural population coherence along this axis, when the local and global spatial reference frames were put in conflict with each other. Proximal CA3 (near the dentate gyrus), where the recurrent collaterals are the weakest, showed degraded representations, similar to the pattern separation shown by the dentate gyrus. Distal CA3 (near CA2), where the recurrent collaterals are the strongest, maintained coherent representations in the conflict situation, resembling the classic attractor network system. CA2 also maintained coherent representations. This dissociation between proximal and distal CA3 provides strong evidence that the recurrent collateral system underlies the associative network functions of CA3, with a separate role of proximal CA3 in pattern separation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Adult hippocampal neurogenesis, the constitutive generation of new granule cells in the dentate gyrus of the mature brain, is a robust model of neural development and its dysregulation has been implicated in the pathogenesis of psychiatric and neurological disorders. Previous studies in mice have shown that altered expression of Disrupted-In-Schizophrenia 1 (Disc1), the mouse homolog of a risk gene for major psychiatric disorders, results in several distinct morphological phenotypes during neuronal development. Although there are advantages to using rats over mice for neurophysiological studies, genetic manipulations have not been widely utilized in rat models. Here, we used a retroviral-mediated approach to knockdown DISC1 expression in dividing cells in the rat dentate gyrus and characterized the morphological development of adult-born granule neurons. Consistent with earlier findings in mice, we show that DISC1 knockdown in adult-born dentate granule cells in rats resulted in accelerated dendritic growth, soma hypertrophy, ectopic dendrites, and mispositioning of new granule cells due to overextended migration. Our study thus demonstrates that the Disc1 genetic manipulation approach used in prior mouse studies is feasible in rats and that there is a conserved biological function of this gene across species. Extending gene-based studies of adult hippocampal neurogenesis from mice to rats will allow for the development of additional models that may be more amenable to behavioral and in vivo electrophysiological investigations. These models, in turn, can generate additional insight into the systems-level mechanisms of how risk genes for complex psychiatric disorders may impact adult neurogenesis and hippocampal function.

A longstanding debate in hippocampus research has revolved around how to reconcile spatial mapping functions of the hippocampus with the global amnesia produced by hippocampal damage in humans. Is the hippocampus primarily a cognitive map used to support spatial learning, or does it support more general types of learning necessary for declarative memory? In recent years, a general consensus has emerged that the hippocampus receives both spatial and nonspatial inputs from the entorhinal cortex. The hippocampus creates representations of experience in a particular spatial and temporal context. This process allows the individual components of experience to be stored in such a way that they can be retrieved together as a conscious recollection., (© 2015 Wiley Periodicals, Inc.)

Grid cells, border cells, head-directions cells, and conjunctive correlates found in the Medial Entorhinal Cortex (MEC) indicate the presence of highly specialized neural circuits that process allocentric space. New technical advancements, as described by Tang et al. (2014) in this issue, offer an integrated approach to charting the function and organization of these circuits., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The hippocampus is thought to have a critical role in episodic memory by incorporating the sensory input of an experience onto a spatial framework embodied by place cells. Although the formation and stability of place fields requires exploration, the interaction between discrete exploratory behaviors and the specific, immediate and persistent modifications of neural representations required by episodic memory has not been established. We recorded place cells in rats and found that increased neural activity during exploratory head-scanning behaviors predicted the formation and potentiation of place fields on the next pass through that location, regardless of environmental familiarity and across multiple testing days. These results strongly suggest that, during the attentive behaviors that punctuate exploration, place cell activity mediates the one-trial encoding of ongoing experiences necessary for episodic memory.

Theories of associative memory suggest that successful memory storage and recall depend on a balance between two complementary processes: pattern separation (to minimize interference) and pattern completion (to retrieve a memory when presented with partial or degraded input cues). Putative attractor circuitry in the hippocampal CA3 region is thought to be the final arbiter between these two processes. Here we present direct, quantitative evidence that CA3 produces an output pattern closer to the originally stored representation than its degraded input patterns from the dentate gyrus (DG). We simultaneously recorded activity from CA3 and DG of behaving rats when local and global reference frames were placed in conflict. CA3 showed a coherent population response to the conflict (pattern completion), even though its DG inputs were severely disrupted (pattern separation). The results thus confirm the hallmark predictions of a longstanding computational model of hippocampal memory processing., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The hippocampus receives its major cortical input from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input. We review new data which suggest that this simple dichotomy between 'where' versus 'what' needs revision. We propose a refinement of this model, which is more complex than the simple spatial-non-spatial dichotomy. MEC is proposed to be involved in path integration computations based on a global frame of reference, primarily using internally generated, self-motion cues and external input about environmental boundaries and scenes; it provides the hippocampus with a coordinate system that underlies the spatial context of an experience. LEC is proposed to process information about individual items and locations based on a local frame of reference, primarily using external sensory input; it provides the hippocampus with information about the content of an experience.

In a surface-dwelling animal like the rat, experimental strategies for investigating the hippocampal correlates of three-dimensional space appear inevitably complicated by the interplay of global versus local reference frames. We discuss the impact of the resulting confounds on present and future empirical analysis of the "bicoded map" hypothesis by Jeffery and colleagues.

Manipulation of spatial reference frames is a common experimental tool to investigate the nature of hippocampal information coding and to investigate high-order processes, such as cognitive coordination. However, it is unknown how the hippocampus afferents represent the local and global reference frames of an environment. To address these issues, single units were recorded in freely moving rats with multi-tetrode arrays targeting the superficial layers of the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two primary cortical inputs to the hippocampus. Rats ran clockwise laps around a circular track partitioned into quadrants covered by different textures (the local reference frame). The track was centered in a circular environment with distinct landmarks on the walls (the global reference frame). Here we demonstrate a novel dissociation between MEC and LEC in that the global frame controlled the MEC representation and the local frame controlled the LEC representation when the reference frames were rotated in equal, but opposite, directions. Consideration of the functional anatomy of the hippocampal circuit and popular models of attractor dynamics in CA3 suggests a mechanistic explanation of previous data showing a dissociation between the CA3 and CA1 regions in their responses to this local-global conflict. Furthermore, these results are consistent with a model of the LEC providing the hippocampus with the external sensory content of an experience and the MEC providing the spatial context, which combine to form conjunctive codes in the hippocampus that form the basis of episodic memory.

The hippocampus is thought to represent nonspatial information in the context of spatial information. An animal can derive both spatial information as well as nonspatial information from the objects (landmarks) it encounters as it moves around in an environment. In this article, correlates of both object-derived spatial as well as nonspatial information in the hippocampus of rats foraging in the presence of objects are demonstrated. A new form of CA1 place cells, called landmark-vector cells, that encode spatial locations as a vector relationship to local landmarks is described. Such landmark vector relationships can be dynamically encoded. Of the 26 CA1 neurons that developed new fields in the course of a day's recording sessions, in eight cases, the new fields were located at a similar distance and direction from a landmark as the initial field was located relative to a different landmark. In addition, object-location memory in the hippocampus is also described. When objects were removed from an environment or moved to new locations, a small number of neurons in CA1 and CA3 increased firing at the locations where the objects used to be. In some neurons, this increase occurred only in one location, indicating object + place conjunctive memory; in other neurons, the increase in firing was seen at multiple locations where an object used to be. Taken together, these results demonstrate that the spatially restricted firing of hippocampal neurons encode multiple types of information regarding the relationship between an animal's location and the location of objects in its environment., (Copyright © 2013 Wiley Periodicals, Inc.)

The medial temporal lobe (MTL) is involved in mnemonic processing. The perirhinal cortex (PRC) plays a role in object recognition memory, while the hippocampus is required for certain forms of spatial memory and episodic memory. The lateral entorhinal cortex (LEC) receives direct projections from PRC and is one of the two major cortical inputs to the hippocampus. The transformations that occur between PRC and LEC neural representations are not well understood. Here, we show that PRC and LEC had similarly high proportions of neurons with object-related activity (PRC 52/94; LEC 72/153), as expected from their locations in the "what" pathway into the hippocampus. However, LEC unit activity showed more spatial stability than PRC unit activity. A minority of LEC neurons showed stable spatial firing fields away from objects; these firing fields strongly resembled hippocampal place fields. None of the PRC neurons showed this place-like firing. None of the PRC or LEC neurons demonstrated the high firing rates associated with interneurons in hippocampus or medial entorhinal cortex, further dissociating this information processing stream from the path-integration based, movement-related processing of the medial entorhinal cortex and hippocampus. These results provide evidence for nonspatial information processing in the PRC-LEC pathway, as well as showing a functional dissociation between PRC and LEC, with more purely nonspatial representations in PRC and combined spatial-nonspatial representations in LEC., (Copyright © 2012 Wiley Periodicals, Inc.)

The hippocampus has long been associated with navigation and spatial representations, but it has been difficult to link directly the neurophysiological correlates of hippocampal place cells with navigational planning and action. In recent years, large-scale population recordings of place cells have revealed that spatial sequences are stored and activated in ways that may support navigational strategies. Plasticity mechanisms allow the hippocampus to store learned sequences of locations that may allow predictions of future locations based on past experience. These sequences can also be activated during navigational behavior in ways that may allow the animal to learn trajectories toward goals. Task-dependent alterations in place cell firing patterns may reflect the operation of the hippocampus in associating locations with navigationally relevant decision variables., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The dentate gyrus (DG) occupies a key position in information flow through the hippocampus. Its principal cell, the granule cell, has spatially selective place fields. However, the behavioral correlates of cells located in the hilus of the rat dentate gyrus are unknown. We report here that cells below the granule layer show spatially selective firing that consists of multiple subfields. Other cells recorded from the DG had single place fields. Compared with cells with multiple fields, cells with single fields fired at lower rates during sleep were less bursty, and were more likely to be recorded simultaneously with large populations of neurons that were active during sleep and silent during behavior. We propose that cells with single fields are likely to be mature granule cells that use sparse encoding to potentially disambiguate input patterns. Furthermore, we hypothesize that cells with multiple fields might be cells of the hilus or newborn granule cells. These data are the first demonstration, based on physiological criteria, that single- and multiple-field cells constitute at least two distinct cell classes in the DG. Because of the heterogeneity of firing correlates and cell types in the DG, understanding which cell types correspond to which firing patterns, and how these correlates change with behavioral state and between different environments, are critical questions for testing long-standing computational theories that the DG performs a pattern separation function using a very sparse coding strategy.

Damage to the hippocampus and related brain regions causes a profound amnesic syndrome, in which patients are unable to form new memories about their experiences and about facts about the world. A number of theories have been proposed to explain hippocampal function. The theories that are currently most influential propose that the hippocampus is the substrate of declarative or episodic memory and that the hippocampus is the neural locus of a cognitive map. Anatomical, physiological, and behavioral studies of the hippocampal system have enabled a rich understanding of a number of general principles of information processing and storage in the brain. In this article, we describe key anatomical and physiological features of hippocampal function as well as the most influential theories of hippocampal function. WIREs Cogn Sci 2012, 3:231-251. doi: 10.1002/wcs.1164 For further resources related to this article, please visit the WIREs website., (Copyright © 2012 John Wiley & Sons, Ltd.)

Insight into the processing dynamics and other neurophysiological properties of different hippocampal subfields is critically important for understanding hippocampal function. In this study, we compared shifts in the center of mass (COM) of CA3 and CA1 place fields in a familiar and completely novel environment. Place fields in CA1 and CA3 were simultaneously recorded as rats ran along a closed loop track in a familiar room followed by a session in a completely novel room. This process was repeated each day over a 4-day period. CA3 place fields shifted backward (opposite to the direction of motion of the rat) only in novel environments. This backward shift gradually diminished across days, as the novel environment became more familiar with repeated exposures. Conversely, CA1 place fields shifted backward across all days in both familiar and novel environments. Prior studies demonstrated that CA1 place fields on average do not exhibit a backward shift during the first exposure to an environment in which the familiar cues are rearranged into a novel configuration, although CA3 place fields showed a strong backward shift. Under the completely novel conditions of the present study, no dissociation was observed between CA3 and CA1 during the first novel session (although a strong dissociation was observed in the familiar sessions and the later novel sessions). In summary, this is the first study to use simultaneous recordings in CA1 and CA3 to compare place field COM shift and other associated properties in truly novel and familiar environments. This study further demonstrates functional differentiation between CA1 and CA3 as the plasticity of CA1 place fields is affected differently by exposure to a completely novel environment in comparison to an altered, familiar environment, whereas the plasticity of CA3 place fields is affected similarly during both types of environmental novelty.

Attractor networks are a popular computational construct used to model different brain systems. These networks allow elegant computations that are thought to represent a number of aspects of brain function. Although there is good reason to believe that the brain displays attractor dynamics, it has proven difficult to test experimentally whether any particular attractor architecture resides in any particular brain circuit. We review models and experimental evidence for three systems in the rat brain that are presumed to be components of the rat's navigational and memory system. Head-direction cells have been modeled as a ring attractor, grid cells as a plane attractor, and place cells both as a plane attractor and as a point attractor. Whereas the models have proven to be extremely useful conceptual tools, the experimental evidence in their favor, although intriguing, is still mostly circumstantial.

The hippocampus is a brain region that is critical for spatial learning, context-dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral EC (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue-deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus-an internal, path-integration system and an external, landmark-based system-it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue-rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions., (Copyright © 2010 Wiley Periodicals, Inc.)

Some theories of memory propose that the hippocampus integrates the individual items and events of experience within a contextual or spatial framework. The hippocampus receives cortical input from two major pathways: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). During exploration in an open field, the firing fields of MEC grid cells form a periodically repeating, triangular array. In contrast, LEC neurons show little spatial selectivity, and it has been proposed that the LEC may provide non-spatial input to the hippocampus. Here, we recorded MEC and LEC neurons while rats explored an open field that contained discrete objects. LEC cells fired selectively at locations relative to the objects, whereas MEC cells were weakly influenced by the objects. These results provide the first direct demonstration of a double dissociation between LEC and MEC inputs to the hippocampus under conditions of exploration typically used to study hippocampal place cells.

The most common behavioral test of hippocampus-dependent, spatial learning and memory is the Morris water task, and the most commonly studied behavioral correlate of hippocampal neurons is the spatial specificity of place cells. Despite decades of intensive research, it is not completely understood how animals solve the water task and how place cells generate their spatially specific firing fields. Based on early work, it has become the accepted wisdom in the general neuroscience community that distal spatial cues are the primary sources of information used by animals to solve the water task (and similar spatial tasks) and by place cells to generate their spatial specificity. More recent research, along with earlier studies that were overshadowed by the emphasis on distal cues, put this common view into question by demonstrating primary influences of local cues and local boundaries on spatial behavior and place-cell firing. This paper first reviews the historical underpinnings of the "standard" view from a behavioral perspective, and then reviews newer results demonstrating that an animal's behavior in such spatial tasks is more strongly controlled by a local-apparatus frame of reference than by distal landmarks. The paper then reviews similar findings from the literature on the neurophysiological correlates of place cells and other spatially correlated cells from related brain areas. A model is proposed by which distal cues primarily set the orientation of the animal's internal spatial coordinate system, via the head direction cell system, whereas local cues and apparatus boundaries primarily set the translation and scale of that coordinate system.

Mammals navigate by integrating self-motion signals ("path integration") and occasionally fixing on familiar environmental landmarks. The rat hippocampus is a model system of spatial representation in which place cells are thought to integrate both sensory and spatial information from entorhinal cortex. The localized firing fields of hippocampal place cells and entorhinal grid-cells demonstrate a phase relationship with the local theta (6-10 Hz) rhythm that may be a temporal signature of path integration. However, encoding self-motion in the phase of theta oscillations requires high temporal precision and is susceptible to idiothetic noise, neuronal variability, and a changing environment. We present a model based on oscillatory interference theory, previously studied in the context of grid cells, in which transient temporal synchronization among a pool of path-integrating theta oscillators produces hippocampal-like place fields. We hypothesize that a spatiotemporally extended sensory interaction with external cues modulates feedback to the theta oscillators. We implement a form of this cue-driven feedback and show that it can retrieve fixed points in the phase code of position. A single cue can smoothly reset oscillator phases to correct for both systematic errors and continuous noise in path integration. Further, simulations in which local and global cues are rotated against each other reveal a phase-code mechanism in which conflicting cue arrangements can reproduce experimentally observed distributions of "partial remapping" responses. This abstract model demonstrates that phase-code feedback can provide stability to the temporal coding of position during navigation and may contribute to the context-dependence of hippocampal spatial representations. While the anatomical substrates of these processes have not been fully characterized, our findings suggest several signatures that can be evaluated in future experiments.