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The hippocampal formation contains neurons responsive to an animal's current location and orientation, which together provide the organism with a neural map of space. 1 , 2 , 3 Spatially tuned neurons rely on external landmark cues and internally generated movement information to estimate position. 4 , 5 An important class of landmark cue are the boundaries delimiting an environment, which can define place cell field position 6 , 7 and stabilize grid cell firing. 8 However, the precise nature of the sensory information used to detect boundaries remains unknown. We used 2-dimensional virtual reality (VR) 9 to show that visual cues from elevated walls surrounding the environment are both sufficient and necessary to stabilize place and grid cell responses in VR, when only visual and self-motion cues are available. By contrast, flat boundaries formed by the edges of a textured floor did not stabilize place and grid cells, indicating only specific forms of visual boundary stabilize hippocampal spatial firing. Unstable grid cells retain internally coherent, hexagonally arranged firing fields, but these fields "drift" with respect to the virtual environment over periods >5 s. Optic flow from a virtual floor does not slow drift dynamics, emphasizing the importance of boundary-related visual information. Surprisingly, place fields are more stable close to boundaries even with floor and wall cues removed, suggesting invisible boundaries are inferred using the motion of a discrete, separate cue (a beacon signaling reward location). Subsets of place cells show allocentric directional tuning toward the beacon, with strength of tuning correlating with place field stability when boundaries are removed., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Path integration (PI) is impaired early in Alzheimer's disease (AD) but reflects multiple sub-processes that may be differentially sensitive to AD. To characterize these sub-processes, we developed a novel generative linear-angular model of PI (GLAMPI) to fit the inbound paths of healthy elderly participants performing triangle completion, a popular PI task, in immersive virtual reality with real movement. The model fits seven parameters reflecting the encoding, calculation, and production errors associated with inaccuracies in PI. We compared these parameters across younger and older participants and patients with mild cognitive impairment (MCI), including those with (MCI+) and without (MCI-) cerebrospinal fluid biomarkers of AD neuropathology. MCI patients showed overestimation of the angular turn in the outbound path and more variable inbound distances and directions compared with healthy elderly. MCI+ were best distinguished from MCI- patients by overestimation of outbound turns and more variable inbound directions. Our results suggest that overestimation of turning underlies the PI errors seen in patients with early AD, indicating specific neural pathways and diagnostic behaviors for further research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuronal "replay," in which place cell firing during rest recapitulates recently experienced trajectories, is thought to mediate the transmission of information from hippocampus to neocortex, but the mechanism for this transmission is unknown. Here, we show that replay uses a phase code to represent spatial trajectories by the phase of firing relative to the 150- to 250-Hz "ripple" oscillations that accompany replay events. This phase code is analogous to the theta phase precession of place cell firing during navigation, in which place cells fire at progressively earlier phases of the 6- to 12-Hz theta oscillation as their place field is traversed, providing information about self-location that is additional to the rate code and a necessary precursor of replay. Thus, during replay, each ripple cycle contains a "forward sweep" of decoded locations along the recapitulated trajectory. Our results indicate a novel encoding of trajectory information during replay and implicates phase coding as a general mechanism by which the hippocampus transmits experienced and replayed sequential information to downstream targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ability to represent and respond to uncertainty is fundamental to human cognition and decision-making. Noradrenaline (NA) is hypothesized to play a key role in coordinating the sensory, learning, and physiological states necessary to adapt to a changing world, but direct evidence for this is lacking in humans. Here, we tested the effects of attenuating noradrenergic neurotransmission on learning under uncertainty. We probed the effects of the β-adrenergic receptor antagonist propranolol (40 mg) using a between-subjects, double-blind, placebo-controlled design. Participants performed a probabilistic associative learning task, and we employed a hierarchical learning model to formally quantify prediction errors about cue-outcome contingencies and changes in these associations over time (volatility). Both unexpectedness and noise slowed down reaction times, but propranolol augmented the interaction between these main effects such that behavior was influenced more by prior expectations when uncertainty was high. Computationally, this was driven by a reduction in learning rates, with people slower to update their beliefs in the face of new information. Attenuating the global effects of NA also eliminated the phasic effects of prediction error and volatility on pupil size, consistent with slower belief updating. Finally, estimates of environmental volatility were predicted by baseline cardiac measures in all participants. Our results demonstrate that NA underpins behavioral and computational responses to uncertainty. These findings have important implications for understanding the impact of uncertainty on human biology and cognition., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

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.)

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.)

Fluent retrieval and execution of movement sequences is essential for daily activities, but the neural mechanisms underlying sequence planning remain elusive. Here participants learned finger press sequences with different orders and timings and reproduced them in a magneto-encephalography (MEG) scanner. We classified the MEG patterns for each press in the sequence and examined pattern dynamics during preparation and production. Our results demonstrate the "competitive queuing" (CQ) of upcoming action representations, extending previous computational and non-human primate recording studies to non-invasive measures in humans. In addition, we show that CQ reflects an ordinal template that generalizes across specific motor actions at each position. Finally, we demonstrate that CQ predicts participants' production accuracy and originates from parahippocampal and cerebellar sources. These results suggest that the brain learns and controls multiple sequences by flexibly combining representations of specific actions and interval timing with high-level, parallel representations of sequence position., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Models of face, object, and scene recognition traditionally focus on massively parallel processing of low-level features, with higher-order representations emerging at later processing stages. However, visual perception is tightly coupled to eye movements, which are necessarily sequential. Recently, neurons in entorhinal cortex have been reported with grid cell-like firing in response to eye movements, i.e., in visual space. Following the presumed role of grid cells in vector navigation, we propose a model of recognition memory for familiar faces, objects, and scenes, in which grid cells encode translation vectors between salient stimulus features. A sequence of saccadic eye-movement vectors, moving from one salient feature to the expected location of the next, potentially confirms an initial hypothesis (accumulating evidence toward a threshold) about stimulus identity, based on the relative feature layout (i.e., going beyond recognition of individual features). The model provides an explicit neural mechanism for the long-held view that directed saccades support hypothesis-driven, constructive perception and recognition; is compatible with holistic face processing; and constitutes the first quantitative proposal for a role of grid cells in visual recognition. The variance of grid cell activity along saccade trajectories exhibits 6-fold symmetry across 360 degrees akin to recently reported fMRI data. The model suggests that disconnecting grid cells from occipitotemporal inputs may yield prosopagnosia-like symptoms. The mechanism is robust with regard to partial visual occlusion, can accommodate size and position invariance, and suggests a functional explanation for medial temporal lobe involvement in visual memory for relational information and memory-guided attention., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In the brain, coding information in the phase of neural firing relative to some baseline oscillation offers numerous theoretical advantages. New research suggests this may occur even when the baseline frequency is highly irregular, as seen in bats and humans., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hinman et al. demonstrate the presence of two speed signals in the rodent medial entorhinal cortex that are differentially affected by muscimol inactivation of medial septum. The results reveal important constraints on several computational models of grid cell firing., (Copyright © 2016. Published by Elsevier Inc.)

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.)

Grid cells in the entorhinal cortex (EC) of rodents [1] and humans [2] fire in a hexagonally distributed spatially periodic manner. In concert with other spatial cells in the medial temporal lobe (MTL) [3-6], they provide a representation of our location within an environment [7, 8] and are specifically thought to allow the represented location to be updated by self-motion [9]. Grid-like signals have been seen throughout the autobiographical memory system [10], suggesting a much more general role in memory [11, 12]. Grid cells may allow us to move our viewpoint in imagination [13], a useful function for goal-directed navigation and planning [12, 14-16], and episodic future thinking more generally [17, 18]. We used fMRI to provide evidence for similar grid-like signals in human entorhinal cortex during both virtual navigation and imagined navigation of the same paths. We show that this signal is present in periods of active navigation and imagination, with a similar orientation in both and with the specifically 6-fold rotational symmetry characteristic of grid cell firing. We therefore provide the first evidence suggesting that grid cells are utilized during movement of viewpoint within imagery, potentially underpinning our more general ability to mentally traverse possible routes in the service of planning and episodic future thinking., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

In this issue of Neuron, Hardcastle et al. (2015) show that the spatial firing patterns of grid cells accumulate error, drifting coherently, until reset by encounters with environmental boundaries. These results reveal important aspects of the neural dynamics of self-localization from self-motion and environmental information., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The firing patterns of grid cells in medial entorhinal cortex (mEC) and associated brain areas form triangular arrays that tessellate the environment [1, 2] and maintain constant spatial offsets to each other between environments [3, 4]. These cells are thought to provide an efficient metric for navigation in large-scale space [5-8]. However, an accurate and universal metric requires grid cell firing patterns to uniformly cover the space to be navigated, in contrast to recent demonstrations that environmental features such as boundaries can distort [9-11] and fragment [12] grid patterns. To establish whether grid firing is determined by local environmental cues, or provides a coherent global representation, we recorded mEC grid cells in rats foraging in an environment containing two perceptually identical compartments connected via a corridor. During initial exposures to the multicompartment environment, grid firing patterns were dominated by local environmental cues, replicating between the two compartments. However, with prolonged experience, grid cell firing patterns formed a single, continuous representation that spanned both compartments. Thus, we provide the first evidence that in a complex environment, grid cell firing can form the coherent global pattern necessary for them to act as a metric capable of supporting large-scale spatial navigation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Understanding how the cognitive functions of the brain arise from its basic physiological components has been an enticing final frontier in science for thousands of years. The Nobel Prize in Physiology or Medicine 2014 was awarded one half to John O'Keefe, the other half jointly to May-Britt Moser and Edvard I. Moser "for their discoveries of cells that constitute a positioning system in the brain." This prize recognizes both a paradigm shift in the study of cognitive neuroscience, and some of the amazing insights that have followed from it concerning how the world is represented within the brain., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.)

Personally experienced events include multiple elements, such as locations, people, and objects. These events are thought to be stored in episodic memory as coherent representations [1] that allow the retrieval of all elements from a partial cue ("pattern completion" [2-6]). However, direct evidence for coherent multielement representations is lacking. Their presence would predict that retrieval of one element from an event should be dependent on retrieval of the other elements from that event. If we remember where we were, we should be more likely to remember who we met and what object they gave us. Here we provide evidence for this type of dependency in remembering three-element events. Dependency was seen when all three elements were encoded simultaneously, or when the three overlapping pairwise associations comprising an event were learned on separate trials. However, dependency was only seen in the separated encoding condition when all possible within-event associations were encoded. These results suggest that episodic memories are stored as coherent representations in which associations between all within-event elements allow retrieval via pattern completion. They also show that related experiences encountered at different times can be flexibly integrated into these coherent representations., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

How does adult neurogenesis contribute to memory? Nakashiba and colleagues generated mutant mice in which synaptic output from older hippocampal granule cells was specifically blocked. Experiments with these mice reveal an unpredicted age-dependent specialization of function, demonstrating that recently born cells support pattern separation, whereas older cells support pattern completion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Finding one's way in a large-scale environment may engage different cognitive processes than following a familiar route. The neural bases of these processes were investigated using functional MRI (fMRI). Subjects found their way in one virtual-reality town and followed a well-learned route in another. In a control condition, subjects followed a visible trail. Within subjects, accurate wayfinding activated the right posterior hippocampus. Between-subjects correlations with performance showed that good navigators (i.e., accurate wayfinders) activated the anterior hippocampus during wayfinding and head of caudate during route following. These results coincide with neurophysiological evidence for distinct response (caudate) and place (hippocampal) representations supporting navigation. We argue that the type of representation used influences both performance and concomitant fMRI activation patterns.

Finding one's way around an environment and remembering the events that occur within it are crucial cognitive abilities that have been linked to the hippocampus and medial temporal lobes. Our review of neuropsychological, behavioral, and neuroimaging studies of human hippocampal involvement in spatial memory concentrates on three important concepts in this field: spatial frameworks, dimensionality, and orientation and self-motion. We also compare variation in hippocampal structure and function across and within species. We discuss how its spatial role relates to its accepted role in episodic memory. Five related studies use virtual reality to examine these two types of memory in ecologically valid situations. While processing of spatial scenes involves the parahippocampus, the right hippocampus appears particularly involved in memory for locations within an environment, with the left hippocampus more involved in context-dependent episodic or autobiographical memory.