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Despite bilateral hippocampal damage dating to the perinatal or early childhood period and severely impaired episodic memory, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganize to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate, and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40%, while the atrophy of the uncus was moderate (-24%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance, viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions. More severe hippocampal damage may be more likely to promote structural and/or functional reorganization in areas connected to the hippocampus. In this hypothesis, different levels of hippocampal function may be rescued following this variable reorganization. Our findings document not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animal's location as a vector displacement from boundaries. Here we characterise the prevalence and spatial tuning of subiculum BVCs in adult and developing male rats, and investigate the relationship between BVC spatial firing and boundary geometry. BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space., (© 2024. The Author(s).)

Humans and other animals use multiple strategies for making decisions. Reinforcement-learning theory distinguishes between stimulus-response (model-free; MF) learning and deliberative (model-based; MB) planning. The spatial-navigation literature presents a parallel dichotomy between navigation strategies. In "response learning," associated with the dorsolateral striatum (DLS), decisions are anchored to an egocentric reference frame. In "place learning," associated with the hippocampus, decisions are anchored to an allocentric reference frame. Emerging evidence suggests that the contribution of hippocampus to place learning may also underlie its contribution to MB learning by representing relational structure in a cognitive map. Here, we introduce a computational model in which hippocampus subserves place and MB learning by learning a "successor representation" of relational structure between states; DLS implements model-free response learning by learning associations between actions and egocentric representations of landmarks; and action values from either system are weighted by the reliability of its predictions. We show that this model reproduces a range of seemingly disparate behavioral findings in spatial and nonspatial decision tasks and explains the effects of lesions to DLS and hippocampus on these tasks. Furthermore, modeling place cells as driven by boundaries explains the observation that, unlike navigation guided by landmarks, navigation guided by boundaries is robust to "blocking" by prior state-reward associations due to learned associations between place cells. Our model, originally shaped by detailed constraints in the spatial literature, successfully characterizes the hippocampal-striatal system as a general system for decision making via adaptive combination of stimulus-response learning and the use of a cognitive map., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains, provide a mechanistic understanding of the hippocampal role in generalization, and offer unifying principles underlying many entorhinal and hippocampal cell types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells display diverse properties resembling apparently bespoke spatial responses, such as grid, band, border, and object-vector cells. TEM hippocampal cells include place and landmark cells that remap between environments. Crucially, TEM also aligns with empirically recorded representations in complex non-spatial tasks. TEM also generates predictions that hippocampal remapping is not random as previously believed; rather, structural knowledge is preserved across environments. We confirm this structural transfer over remapping in simultaneously recorded place and grid cells., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes. One notable example is provided by place and grid cells in the rodent hippocampal formation, which exhibit phase precession-firing at progressively earlier phases of the 6-12 Hz movement-related theta rhythm as their spatial firing fields are traversed. It is often assumed that such phase coding relies on a high amplitude baseline oscillation with relatively constant frequency. However, sustained oscillations with fixed frequency are generally absent in LFP and spike train recordings from the human brain. Hence, we examine phase coding relative to LFP signals with broadband low-frequency (2-20 Hz) power but without regular rhythmicity. We simulate a population of grid cells that exhibit phase precession against a baseline oscillation recorded from depth electrodes in human hippocampus. We show that this allows grid cell firing patterns to multiplex information about location, running speed and movement direction, alongside an arbitrary fourth variable encoded in LFP frequency. This is of particular importance given recent demonstrations that movement direction, which is essential for path integration, cannot be recovered from head direction cell firing rates. In addition, we investigate how firing phase might reduce errors in decoded location, including those arising from differences in firing rate across grid fields. Finally, we describe analytical methods that can identify phase coding in the absence of high amplitude LFP oscillations with approximately constant frequency, as in single unit recordings from the human brain and consistent with recent data from the flying bat. We note that these methods could also be used to detect phase coding outside of the spatial domain, and that multi-unit activity can substitute for the LFP signal. In summary, we demonstrate that the computational advantages offered by phase coding are not contingent on, and can be detected without, regular rhythmicity in neural activity., (© 2020 The Authors. Hippocampus published by Wiley Periodicals, Inc.)

Hippocampal formation contains several classes of neurons thought to be involved in navigational processes, in particular place cells and grid cells. Place cells have been associated with a topological strategy for navigation, while grid cells have been suggested to support metric vector navigation. Grid cell-based vector navigation can support novel shortcuts across unexplored territory by providing the direction toward the goal. However, this strategy is insufficient in natural environments cluttered with obstacles. Here, we show how navigation in complex environments can be supported by integrating a grid cell-based vector navigation mechanism with local obstacle avoidance mediated by border cells and place cells whose interconnections form an experience-dependent topological graph of the environment. When vector navigation and object avoidance fail (i.e., the agent gets stuck), place cell replay events set closer subgoals for vector navigation. We demonstrate that this combined navigation model can successfully traverse environments cluttered by obstacles and is particularly useful where the environment is underexplored. Finally, we show that the model enables the simulated agent to successfully navigate experimental maze environments from the animal literature on cognitive mapping. The proposed model is sufficiently flexible to support navigation in different environments, and may inform the design of experiments to relate different navigational abilities to place, grid, and border cell firing., (© 2019 The Authors. Hippocampus published by Wiley Periodicals, Inc.)

Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cognitive disturbances occur early in Huntington's disease (HD) and place a significant burden on the lives of patients and family members. Whilst these impairments are typically attributed to deterioration of the frontal-striatal pathways, accumulating evidence suggests that hippocampal dysfunction may also contribute to such impairments. Here, we employ a novel spatial memory task that has previously been shown to elicit impairments in individuals with focal hippocampal lesions, as a means to further investigate the role of hippocampal dysfunction in HD., Method: Sixty-four individuals participated in the study, including 32 healthy controls, 11 patients with diagnosed HD and 16 premanifest HD gene carriers. We also included an additional control group of 5 individuals with focal unilateral basal ganglia lesions. Participants undertook a task that measured perception and short-term spatial memory using computer-generated visual scenes., Results: HD patients experienced significant impairments in spatial perception and memory, which strongly correlated with disease burden score (DBS). Premanifest gene carriers performed at a similar level to healthy controls throughout all aspects of the task indicating that the effects seen in the HD patients represent a deterioration in function. Interestingly, basal ganglia lesion patients were not impaired in any aspects of the task., Conclusion: There is evidence of significant deficits in hippocampal-dependent spatial cognition in HD that cannot be explained as a function of degeneration to the basal ganglia. The impairments were greatest in individuals with higher DBSs, suggesting that deficits relate to the disease process in HD., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Place cells and grid cells in the hippocampal formation are thought to integrate sensory and self-motion information into a representation of estimated spatial location, but the precise mechanism is unknown. We simulated a parallel attractor system in which place cells form an attractor network driven by environmental inputs and grid cells form an attractor network performing path integration driven by self-motion, with inter-connections between them allowing both types of input to influence firing in both ensembles. We show that such a system is needed to explain the spatial patterns and temporal dynamics of place cell firing when rats run on a linear track in which the familiar correspondence between environmental and self-motion inputs is changed. In contrast, the alternative architecture of a single recurrent network of place cells (performing path integration and receiving environmental inputs) cannot reproduce the place cell firing dynamics. These results support the hypothesis that grid and place cells provide two different but complementary attractor representations (based on self-motion and environmental sensory inputs, respectively). Our results also indicate the specific neural mechanism and main predictors of hippocampal map realignment and make predictions for future studies., (Copyright © 2019 Laptev and Burgess.)

Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present a mouse virtual reality (VR) system which restrains head-movements to horizontal rotations, compatible with multi-photon imaging. This system allows expression of the spatial navigation and neuronal firing patterns characteristic of real open arenas (R). Comparing VR to R: place and grid, but not head-direction, cell firing had broader spatial tuning; place, but not grid, cell firing was more directional; theta frequency increased less with running speed, whereas increases in firing rates with running speed and place and grid cells' theta phase precession were similar. These results suggest that the omni-directional place cell firing in R may require local-cues unavailable in VR, and that the scale of grid and place cell firing patterns, and theta frequency, reflect translational motion inferred from both virtual (visual and proprioceptive) and real (vestibular translation and extra-maze) cues. By contrast, firing rates and theta phase precession appear to reflect visual and proprioceptive cues alone., Competing Interests: GC, JK, YL, FC No competing interests declared, NB Reviewing editor, eLife, (© 2018, Chen et al.)

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders., Competing Interests: The authors declare no conflict of interest.

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a self-paced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movement-onset periods are associated with a significant increase in both low (2-5 Hz)- and high (6-9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation., Competing Interests: The authors declare no conflict of interest.

Memories are thought to be retrieved by attractor dynamics if a given input is sufficiently similar to a stored attractor state [1-5]. The hippocampus, a region crucial for spatial navigation [6-12] and episodic memory [13-18], has been associated with attractor-based computations [5, 9], receiving support from the way rodent place cells "remap" nonlinearly between spatial representations [19-22]. In humans, nonlinear response patterns have been reported in perceptual categorization tasks [23-25]; however, it remains elusive whether human memory retrieval is driven by attractor dynamics and what neural mechanisms might underpin them. To test this, we used a virtual reality [7, 11, 26-28] task where participants learned object-location associations within two distinct virtual reality environments. Participants were subsequently exposed to four novel intermediate environments, generated by linearly morphing the background landscapes of the familiar environments, while tracking fMRI activity. We show that linear changes in environmental context cause linear changes in activity patterns in sensory cortex but cause dynamic, nonlinear changes in both hippocampal activity pattern and remembered locations. Furthermore, the sigmoidal response in the hippocampus scaled with the strength of the sigmoidal pattern in spatial memory. These results indicate that mnemonic decisions in an ambiguous novel context relate to putative attractor dynamics in the hippocampus, which support the dynamic remapping of memories., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although negative emotion can strengthen memory of an event it can also result in memory disturbances, as in post-traumatic stress disorder (PTSD). We examined the effects of negative item content on amygdalar and hippocampal function in memory for the items themselves and for the associations between them. During fMRI, we examined encoding and retrieval of paired associates made up of all four combinations of neutral and negative images. At test, participants were cued with an image and, if recognised, had to retrieve the associated (target) image. The presence of negative images increased item memory but reduced associative memory. At encoding, subsequent item recognition correlated with amygdala activity, while subsequent associative memory correlated with hippocampal activity. Hippocampal activity was reduced by the presence of negative images, during encoding and correct associative retrieval. In contrast, amygdala activity increased for correctly retrieved negative images, even when cued by a neutral image. Our findings support a dual representation account, whereby negative emotion up-regulates the amygdala to strengthen item memory but down-regulates the hippocampus to weaken associative representations. These results have implications for the development and treatment of clinical disorders in which diminished associations between emotional stimuli and their context contribute to negative symptoms, as in PTSD., (© The Author (2016). Published by Oxford University Press.)

To examine the cerebellar contribution to human spatial navigation we used functional magnetic resonance imaging and virtual reality. Our findings show that the sensory-motor requirements of navigation induce activity in cerebellar lobules and cortical areas known to be involved in the motor loop and vestibular processing. By contrast, cognitive aspects of navigation mainly induce activity in a different cerebellar lobule (VIIA Crus I). Our results demonstrate a functional link between cerebellum and hippocampus in humans and identify specific functional circuits linking lobule VIIA Crus I of the cerebellum to medial parietal, medial prefrontal, and hippocampal cortices in nonmotor aspects of navigation. They further suggest that Crus I belongs to 2 nonmotor loops, involved in different strategies: place-based navigation is supported by coherent activity between left cerebellar lobule VIIA Crus I and medial parietal cortex along with right hippocampus activity, while sequence-based navigation is supported by coherent activity between right lobule VIIA Crus I, medial prefrontal cortex, and left hippocampus. These results highlight the prominent role of the human cerebellum in both motor and cognitive aspects of navigation, and specify the cortico-cerebellar circuits by which it acts depending on the requirements of the task., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with "moderate" hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes., Significance Statement: In humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated spatial recall using a virtual environment in two groups of patients with hippocampal damage (moderate/severe) and a normal control group. The results showed that patients with severe hippocampal damage are impaired in learning and recalling allocentric spatial information. Furthermore, hippocampal volume reduction impaired allocentric navigation beyond what can be predicted by memory quotient as a widely used measure of general memory function., (Copyright © 2015 Guderian et al.)

Spatial navigation can serve as a model system in cognitive neuroscience, in which specific neural representations, learning rules, and control strategies can be inferred from the vast experimental literature that exists across many species, including humans. Here, we review this literature, focusing on the contributions of hippocampal and striatal systems, and attempt to outline a minimal cognitive architecture that is consistent with the experimental literature and that synthesizes previous related computational modeling. The resulting architecture includes striatal reinforcement learning based on egocentric representations of sensory states and actions, incidental Hebbian association of sensory information with allocentric state representations in the hippocampus, and arbitration of the outputs of both systems based on confidence/uncertainty in medial prefrontal cortex. We discuss the relationship between this architecture and learning in model-free and model-based systems, episodic memory, imagery, and planning, including some open questions and directions for further experiments., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mammals are able to navigate to hidden goal locations by direct routes that may traverse previously unvisited terrain. Empirical evidence suggests that this "vector navigation" relies on an internal representation of space provided by the hippocampal formation. The periodic spatial firing patterns of grid cells in the hippocampal formation offer a compact combinatorial code for location within large-scale space. Here, we consider the computational problem of how to determine the vector between start and goal locations encoded by the firing of grid cells when this vector may be much longer than the largest grid scale. First, we present an algorithmic solution to the problem, inspired by the Fourier shift theorem. Second, we describe several potential neural network implementations of this solution that combine efficiency of search and biological plausibility. Finally, we discuss the empirical predictions of these implementations and their relationship to the anatomy and electrophysiology of the hippocampal formation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Recollection is thought to be the hallmark of episodic memory. Here we provide evidence that the hippocampus binds together the diverse elements forming an event, allowing holistic recollection via pattern completion of all elements. Participants learn complex 'events' from multiple overlapping pairs of elements, and are tested on all pairwise associations. At encoding, element 'types' (locations, people and objects/animals) produce activation in distinct neocortical regions, while hippocampal activity predicts memory performance for all within-event pairs. When retrieving a pairwise association, neocortical activity corresponding to all event elements is reinstated, including those incidental to the task. Participant's degree of incidental reinstatement correlates with their hippocampal activity. Our results suggest that event elements, represented in distinct neocortical regions, are bound into coherent 'event engrams' in the hippocampus that enable episodic recollection--the re-experiencing or holistic retrieval of all aspects of an event--via a process of hippocampal pattern completion and neocortical reinstatement.

The detection and processing of novel information encountered as we explore our environment is crucial for learning and adaptive behavior. The human hippocampus has been strongly implicated in laboratory tests of novelty detection and episodic memory, but has been less well studied during more ethological tasks such as spatial navigation, typically used in animals. We examined fMRI BOLD activity as a function of environmental and object novelty as humans performed an object-location virtual navigation task. We found greater BOLD response to novel relative to familiar environments in the hippocampus and adjacent parahippocampal gyrus. Object novelty was associated with increased activity in the posterior parahippocampal/fusiform gyrus and anterior hippocampus extending into the amygdala and superior temporal sulcus. Importantly, whilst mid-posterior hippocampus was more sensitive to environmental novelty than object novelty, the anterior hippocampus responded similarly to both forms of novelty. Amygdala activity showed an increase for novel objects that decreased linearly over the learning phase. By investigating how participants learn and use different forms of information during spatial navigation, we found that medial temporal lobe (MTL) activity reflects both the novelty of the environment and of the objects located within it. This novelty processing is likely supported by distinct, but partially overlapping, sets of regions within the MTL., (© 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.)

Brandon et al. (2014) show that the formation of place cell representations in new environments is preserved under septal inactivation, and is thus likely independent of the hippocampal theta rhythm and, by implication, the firing of entorhinal grid cells and the process of path integration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The ability to self-localise and to navigate to remembered goals in complex and changeable environments is crucial to the survival of many mobile species. Electrophysiological investigations of the mammalian hippocampus and associated brain structures have identified several classes of neurons which represent information about an organism's position and orientation. These include place cells, grid cells, head direction cells, and boundary vector cells, as well as cells representing aspects of self-motion. Understanding how these neural representations are formed and updated from environmental sensory information and from information relating to self-motion is an important topic attracting considerable current interest. Here we review the computational mechanisms thought to underlie the formation of these different spatial representations, the interactions between them, and their use in guiding behaviour. These include some of the clearest examples of computational mechanisms of general interest to neuroscience, such as attractor dynamics, temporal coding and multi-modal integration. We also discuss the close relationships between computational modelling and experimental research which are driving progress in this area., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The unitary firing fields of hippocampal place cells are commonly assumed to be generated by input from entorhinal grid cell modules with differing spatial scales. Here, we review recent research that brings this assumption into doubt. Instead, we propose that place cell spatial firing patterns are determined by environmental sensory inputs, including those representing the distance and direction to environmental boundaries, while grid cells provide a complementary self-motion related input that contributes to maintaining place cell firing. In this view, grid and place cell firing patterns are not successive stages of a processing hierarchy, but complementary and interacting representations that work in combination to support the reliable coding of large-scale space., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Over the past four decades, research has revealed that cells in the hippocampal formation provide an exquisitely detailed representation of an animal's current location and heading. These findings have provided the foundations for a growing understanding of the mechanisms of spatial cognition in mammals, including humans. We describe the key properties of the major categories of spatial cells: place cells, head direction cells, grid cells and boundary cells, each of which has a characteristic firing pattern that encodes spatial parameters relating to the animal's current position and orientation. These properties also include the theta oscillation, which appears to play a functional role in the representation and processing of spatial information. Reviewing recent work, we identify some themes of current research and introduce approaches to computational modelling that have helped to bridge the different levels of description at which these mechanisms have been investigated. These range from the level of molecular biology and genetics to the behaviour and brain activity of entire organisms. We argue that the neuroscience of spatial cognition is emerging as an exceptionally integrative field which provides an ideal test-bed for theories linking neural coding, learning, memory and cognition.

The spatial mapping function of the hippocampal formation is likely derived from two sets of information: one based on the external environment and the other based on self-motion. Here, we further characterize 'boundary vector cells' (BVCs) in the rat subiculum, which code space relative to one type of cue in the external environment: boundaries. We find that the majority of cells with fields near the perimeter of a walled environment exhibit an additional firing field when an upright barrier is inserted into the walled environment in a manner predicted by the BVC model. We use this property of field repetition as a heuristic measure to define BVCs, and characterize their spatial and temporal properties. In further tests, we find that subicular BVCs typically treat drop edges similarly to walls, including exhibiting field repetition when additional drop-type boundaries are added to the testing environment. In other words, BVCs treat both kinds of edge as environmental boundaries, despite their dissimilar sensory properties. Finally, we also report the existence of 'boundary-off cells', a new class of boundary-coding cells. These cells fire everywhere except where a given BVC might fire.

The hippocampus is thought to be an associative memory "convergence zone," binding together the multimodal elements of an experienced event into a single engram. This predicts a degree of dependency between the retrieval of the different elements comprising an event. We present data from a series of studies designed to address this prediction. Participants vividly imagined a series of person-location-object events, and memory for these events was assessed across multiple trials of cued retrieval. Consistent with the prediction, a significant level of dependency was found between the retrieval of different elements from the same event. Furthermore, the level of dependency was sensitive both to retrieval task, with higher dependency during cued recall than cued recognition, and to subjective confidence. We propose a simple model, in which events are stored as multiple pairwise associations between individual event elements, and dependency is captured by a common factor that varies across events. This factor may relate to between-events modulation of the strength of encoding, or to a process of within-event "pattern completion" at retrieval. The model predicts the quantitative pattern of dependency in the data when changes in the level of guessing with retrieval task and confidence are taken into account. Thus, we find direct behavioral support for the idea that memory for complex multimodal events depends on the pairwise associations of their constituent elements and that retrieval of the various elements corresponding to the same event reflects a common factor that varies from event to event., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell "remapping."

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion.

How do external environmental and internal movement-related information combine to tell us where we are? We examined the neural representation of environmental location provided by hippocampal place cells while mice navigated a virtual reality environment in which both types of information could be manipulated. Extracellular recordings were made from region CA1 of head-fixed mice navigating a virtual linear track and running in a similar real environment. Despite the absence of vestibular motion signals, normal place cell firing and theta rhythmicity were found. Visual information alone was sufficient for localized firing in 25% of place cells and to maintain a local field potential theta rhythm (but with significantly reduced power). Additional movement-related information was required for normally localized firing by the remaining 75% of place cells. Trials in which movement and visual information were put into conflict showed that they combined nonlinearly to control firing location, and that the relative influence of movement versus visual information varied widely across place cells. However, within this heterogeneity, the behavior of fully half of the place cells conformed to a model of path integration in which the presence of visual cues at the start of each run together with subsequent movement-related updating of position was sufficient to maintain normal fields.

The hippocampal formation plays key roles in representing an animal's location and in detecting environmental novelty to create or update those representations. However, the mechanisms behind this latter function are unclear. Here, we show that environmental novelty causes the spatial firing patterns of grid cells to expand in scale and reduce in regularity, reverting to their familiar scale as the environment becomes familiar. Simultaneously recorded place cell firing fields remapped and showed a smaller, temporary expansion. Grid expansion provides a potential mechanism for novelty signaling and may enhance the formation of new hippocampal representations, whereas the subsequent slow reduction in scale provides a potential familiarity signal.

The mammalian hippocampal formation provides neuronal representations of environmental location, but the underlying mechanisms are poorly understood. Here, we report a class of cells whose spatially periodic firing patterns are composed of plane waves (or bands) drawn from a discrete set of orientations and wavelengths. The majority of cells recorded in parasubicular and medial entorhinal cortices of freely moving rats belonged to this class and included grid cells, an important subset that corresponds to three bands at 60° orientations and has the most stable firing pattern. Occasional changes between hexagonal and nonhexagonal patterns imply a common underlying mechanism. Our results indicate a Fourier-like spatial analysis underlying neuronal representations of location, and suggest that path integration is performed by integrating displacement along a restricted set of directions.

The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning., Competing Interests: The authors have declared that no competing interests exist.

Neuronal firing in the hippocampal formation (HF) of freely moving rodents shows striking examples of spatialorganization in the form of place, directional, boundary vector and grid cells. The firing of place and grid cells shows an intriguing form of temporal organization known as 'theta phase precession'. We review the mechanisms underlying theta phase precession of place cell firing, ranging from membrane potential oscillations to recurrent connectivity, and the relevant intra-cellular and extra-cellular data. We then consider the use of these models to explain the spatial structure of grid cell firing, and review the relevant intra-cellular and extra-cellular data. Finally, we consider the likely interaction between place cells, grid cells and boundary vector cells in estimating self-location as a compromise between path-integration and environmental information., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Planning spatial paths through our environment is an important part of everyday life and is supported by a neural system including the hippocampus and prefrontal cortex. Here we investigated the precise functional roles of the components of this system in humans by using fMRI as participants performed a simple goal-directed route-planning task. Participants had to choose the shorter of two routes to a goal in a visual scene that might contain a barrier blocking the most direct route, requiring a detour, or might be obscured by a curtain, requiring memory for the scene. The participant's start position was varied to parametrically manipulate their proximity to the goal and the difference in length of the two routes. Activity in medial prefrontal cortex, precuneus, and left posterior parietal cortex was associated with detour planning, regardless of difficulty, whereas activity in parahippocampal gyrus was associated with remembering the spatial layout of the visual scene. Activity in bilateral anterior hippocampal formation showed a strong increase the closer the start position was to the goal, together with medial prefrontal, medial and posterior parietal cortices. Our results are consistent with computational models in which goal proximity is used to guide subsequent navigation and with the association of anterior hippocampal areas with nonspatial functions such as arousal and reward expectancy. They illustrate how spatial and nonspatial functions combine within the anterior hippocampus, and how these functions interact with parahippocampal, parietal, and prefrontal areas in decision making and mnemonic function.

When we visualize scenes, either from our own past or invented, we impose a viewpoint for our "mind's eye" and we experience the resulting image as spatially coherent from that viewpoint. The hippocampus has been implicated in this process, but its precise contribution is unknown. We tested a specific hypothesis based on the spatial firing properties of neurons in the hippocampal formation of rats, that this region supports the construction of spatially coherent mental images by representing the locations of the environmental boundaries surrounding our viewpoint. Using functional magnetic resonance imaging, we show that hippocampal activation increases parametrically with the number of enclosing boundaries in the imagined scene. In contrast, hippocampal activity is not modulated by a nonspatial manipulation of scene complexity nor to increasing difficulty of imagining the scenes in general. Our findings identify a specific computational role for the hippocampus in mental imagery and episodic recollection.

The hippocampus is crucial for both spatial navigation and episodic memory, suggesting that it provides a common function to both. Here we adapt a spatial paradigm, developed for rodents, for use with functional MRI in humans to show that activation of the right hippocampus predicts the use of an allocentric spatial representation, and activation of the left hippocampus predicts the use of a sequential egocentric representation. Both representations can be identified in hippocampal activity before their effect on behavior at subsequent choice-points. Our results suggest that, rather than providing a single common function, the two hippocampi provide complementary representations for navigation, concerning places on the right and temporal sequences on the left, both of which likely contribute to different aspects of episodic memory.

The mechanism supporting the role of the hippocampal formation in novelty detection remains controversial. A comparator function has been variously ascribed to CA1 or subiculum, whereas the theta rhythm has been suggested to separate neural firing into encoding and retrieval phases. We investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty-induced plasticity in CA1.

"Boundary vector cells" were predicted to exist by computational models of the environmental inputs underlying the spatial firing patterns of hippocampal place cells (O'Keefe and Burgess, 1996; Burgess et al., 2000; Hartley et al., 2000). Here, we report the existence of cells fulfilling this description in recordings from the subiculum of freely moving rats. These cells may contribute environmental information to place cell firing, complementing path integrative information. Their relationship to other cell types, including medial entorhinal "border cells," is discussed.

Bilateral damage to the human hippocampus profoundly impairs the ability to form long-term, consciously accessible memories, producing a classic amnesic syndrome. However, the effect of hippocampal damage on our ability to recognize items via a feeling of familiarity is hotly disputed. Dual-process theory predicts no effect, whereas declarative memory theory predicts impairment of all types of recognition memory. Here, we demonstrate a striking material specificity in the effect of focal hippocampal damage: Recognition memory is impaired for words but intact for faces. The latter finding is incompatible with declarative memory theory, whereas the former constrains dual-process theory by revealing the limitations of postulated extrahippocampal familiarity-based processes. We suggest that the hippocampus boosts recognition of well-known stimuli (high-frequency words) by activating pre-experimental associations that enrich the context of their presentation. By contrast, recognition memory for some kinds of previously unfamiliar stimuli (unfamiliar faces) may be supported by extrahippocampal familiarity-based processes, at least over short intervals.

How the memory systems centered on the hippocampus and dorsal striatum interact to support behavior remains controversial. We used functional MRI while people learned the locations of objects by collecting and replacing them over multiple trials within a virtual environment comprising a landmark, a circular boundary, and distant cues for orientation. The relative location of landmark and boundary was occasionally changed, with specific objects paired with one or other cue, allowing dissociation of learning and performance relative to either cue. Right posterior hippocampal activation reflected learning and remembering of boundary-related locations, whereas right dorsal striatal activation reflected learning and remembering of landmark-related locations. Within the right hippocampus, anterior processing of environmental change (spatial novelty) was dissociated from posterior processing of location. Behavioral studies show that landmark-related learning obeys associative reinforcement, whereas boundary-related learning is incidental [Doeller CF, Burgess N (2008) Proc Natl Acad Sci USA 105:5909-5914]. The distinct incidental hippocampal processing of boundaries is suggestive of a "geometric module" or "cognitive map" and may explain the hippocampal support of incidental/observational learning in "declarative" or "episodic" memory versus the striatal support of trial-and-error learning in "procedural" memory. Finally, the hippocampal and striatal systems appear to combine "bottom-up," simply influencing behavior proportional to their activations, without direct interaction, with "top-down" ventromedial prefrontal involvement when both are similarly active.

Item recognition for unfamiliar faces and scenes was tested in Jon, who has developmental amnesia resulting from bilateral hippocampal pathology. Performance and confidence judgements in healthy adults showed that both tests were equated for difficulty and had similar receiver operating characteristics (ROCs). Jon's performance on the faces test was indistinguishable from the controls, in both sensitivity and the shape of the ROC curve. In contrast his performance on the scenes test was markedly poor, and his ROC was inconsistent with both a standard dual process (DP; recollection and familiarity) model and an unequal variance signal detection model of recognition memory. Jon's data were as well fitted as controls' data by a DP model that included two recollection parameters, but required counter-intuitive parameter values corresponding to normal recollection and impaired familiarity, which likely reflect an idiosyncratic use of confidence judgements when his memory for the material is weak. The results highlight a limitation in using ROCs to estimate recollection and familiarity in patients who may have developed compensatory strategies for material that they have difficulty remembering (scenes, but not faces in this case). Overall, these data are difficult to reconcile with domain-general accounts of the hippocampal role in memory, including dual process models and the declarative model. Instead, the data indicate that the hippocampus plays a preferential role in the processing of topographical memoranda over faces memoranda.

The hippocampus appears to be crucial for long-term episodic memory, yet its precise role remains elusive. Electrophysiological studies in rodents offer a useful starting point for developing models of hippocampal processing in the spatial domain. Here we review one such model that points to an essential role for the hippocampus in the construction of mental images. We explain how this neural-level mechanistic account addresses some of the current controversies in the field, such as the role of the hippocampus in imagery and short-term memory, and discuss its broader implications for the neural bases of episodic memory.

The hippocampal formation (HF) plays a key role in novelty detection, but the mechanisms remain unknown. Novelty detection aids the encoding of new information into memory-a process thought to depend on the HF and to be modulated by the theta rhythm of EEG. We examined EEG recorded in the HF of rats foraging for food within a novel environment, as it became familiar over the next five days, and in two more novel environments unexpectedly experienced in trials interspersed with familiar trials over three further days. We found that environmental novelty produces a sharp reduction in the theta frequency of foraging rats, that this reduction is greater for an unexpected environment than for a completely novel one, and that it slowly disappears with increasing familiarity. These results do not reflect changes in running speed and suggest that the septo-hippocampal system signals unexpected environmental change via a reduction in theta frequency. In addition, they provide evidence in support of a cholinergically mediated mechanism for novelty detection, have important implications for our understanding of oscillatory coding within memory and for the interpretation of event-related potentials, and provide indirect support for the oscillatory interference model of grid cell firing in medial entorhinal cortex., ((c) 2007 Wiley-Liss, Inc.)

The hippocampus plays a crucial role within the neural systems for long-term memory, but little if any role in the short-term retention of some types of stimuli. Nonetheless, the hippocampus may be specialized for allocentric topographical processing, which impacts on short-term memory or even perception. To investigate this we developed performance-matched tests of perception (match-to-sample) and short-term memory (2 s delayed-match-to-sample) for the topography and for the nonspatial aspects of visual scenes. Four patients with focal hippocampal damage and one with more extensive damage, including right parahippocampal gyrus, were tested. All five patients showed impaired topographical memory and spared nonspatial processing in both memory and perception. Topographical perception was profoundly impaired in the patient with parahippocampal damage, mildly impaired in two of the hippocampal cases, and clearly preserved in the other two hippocampal cases (including one with dense amnesia). Our results suggest that the hippocampus supports allocentric topographical processing that is indispensable when appropriately tested after even very short delays, while the presence of the sample scene can allow successful topographical perception without it, possibly via a less flexible parahippocampal representation.

We review evidence for the boundary vector cell model of the environmental determinants of the firing of hippocampal place cells. Preliminary experimental results are presented concerning the effects of addition or removal of environmental boundaries on place cell firing and evidence that boundary vector cells may exist in the subiculum. We review and update computational simulations predicting the location of human search within a virtual environment of variable geometry, assuming that boundary vector cells provide one of the input representations of location used in mammalian spatial memory. Finally, we extend the model to include experience-dependent modification of connection strengths through a BCM-like learning rule - the size and sign of strength change is influenced by historic activity of the postsynaptic cell. Simulations are compared to experimental data on the firing of place cells under geometrical manipulations to their environment. The relationship between neurophysiological results in rats and spatial behaviour in humans is discussed.

The cognitive processes supporting spatial navigation are considered in the context of a patient (CF) with possible very early Alzheimer's disease who presents with topographical disorientation. Her verbal memory and her recognition memory for unknown buildings, landmarks and outdoor scenes was intact, although she showed an impairment in face processing. By contrast, her navigational ability, quantitatively assessed within a small virtual reality (VR) town, was significantly impaired. Interestingly, she showed a selective impairment in a VR object-location memory test whenever her viewpoint was shifted between presentation and test, but not when tested from the same viewpoint. We suggest that a specific impairment in locating objects relative to the environment rather than relative to the perceived viewpoint (i.e. allocentric rather than egocentric spatial memory) underlies her topographical disorientation. We discuss the likely neural bases of this deficit in the light of related studies in humans and animals, focusing on the hippocampus and related areas. The specificity of our test indicates a new way of assessing topographical disorientation, with possible application to the assessment of progressive dementias such as Alzheimer's disease.

Memories are thought to be attractor states of neuronal representations, with the hippocampus a likely substrate for context-dependent episodic memories. However, such states have not been directly observed. For example, the hippocampal place cell representation of location was previously found to respond continuously to changes in environmental shape alone. We report that exposure to novel square and circular environments made of different materials creates attractor representations for both shapes: Place cells abruptly and simultaneously switch between representations as environmental shape changes incrementally. This enables study of attractor dynamics in a cognitive representation and may correspond to the formation of distinct contexts in context-dependent memory.

We review the ideas and data behind the hypothesis that hippocampal pyramidal cells encode information by their phase of firing relative to the theta rhythm of the EEG. Particular focus is given to the further hypothesis that variations in firing rate can encode information independently from that encoded by firing phase. We discuss possible explanation of the phase-precession effect in terms of interference between two independent oscillatory influences on the pyramidal cell membrane potential, and the extent to which firing phase reflects internal dynamics or external (environmental) variables. Finally, we propose a model of the firing of the recently discovered "grid cells" in entorhinal cortex as part of a path-integration system, in combination with place cells and head-direction cells., (Copyright 2005 Wiley-Liss, Inc.)

The heterogeneous sampling of behavioral states by freely moving animals hinders our ability to relate neuronal firing rates to behavioral variables by introducing dependencies between them. We specifically consider the animal's location and orientation, although our analyses may generalize to other behavioral variables, such as speed of movement. A maximum-likelihood approach is presented for producing estimates of the separate histograms relating firing rate to multiple independent causes. Examples show that the method can be used to avoid the artifactual behavioral correlates of place and head direction-cell firing produced by standard analyses; to characterize the independent influences of both location and orientation in a third cell type (Cacucci et al., 2004); and to demonstrate the location-independence of the directional firing of head-direction cells., ((c) 2004 Wiley-Liss, Inc.)