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Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing social stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

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Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here, we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between 'bimodal cells' showing interleaved phase precession and procession, and 'unimodal cells' in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells' firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.

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The hippocampus is indispensable for episodic memories, but its particular role in the process is still unclear. This chapter briefly overviews past studies focusing on place cells and memory engrams, highlighting their potential roles in spatial navigation. Future work reconciling these two lines of studies would provide a comprehensive view of the specific contribution of the hippocampus and a better understanding of how memory engrams support memory.

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During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

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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 position6,7 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.

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Introduction: Recent work on bats flying over long distances has revealed that single hippocampal cells have multiple place fields of different sizes. At the network level, a multi-scale, multi-field place cell code outperforms classical single-scale, single-field place codes, yet the performance boundaries of such a code remain an open question. In particular, it is unknown how general multi-field codes compare to a highly regular grid code, in which cells form distinct modules with different scales. Methods: In this work, we address the coding properties of theoretical spatial coding models with rigorous analyses of comprehensive simulations. Starting from a multi-scale, multi-field network, we performed evolutionary optimization. The resulting multi-field networks sometimes retained the multi-scale property at the single-cell level but most often converged to a single scale, with all place fields in a given cell having the same size. We compared the results against a single-scale single-field code and a one-dimensional grid code, focusing on two main characteristics: the performance of the code itself and the dynamics of the network generating it. Results: Our simulation experiments revealed that, under normal conditions, a regular grid code outperforms all other codes with respect to decoding accuracy, achieving a given precision with fewer neurons and fields. In contrast, multi-field codes are more robust against noise and lesions, such as random drop-out of neurons, given that the significantly higher number of fields provides redundancy. Contrary to our expectations, the network dynamics of all models, from the original multi-scale models before optimization to the multi-field models that resulted from optimization, did not maintain activity bumps at their original locations when a position-specific external input was removed. Discussion: Optimized multi-field codes appear to strike a compromise between a place code and a grid code that reflects a trade-off between accurate positional encoding and robustness. Surprisingly, the recurrent neural network models we implemented and optimized for either multi- or single-scale, multi-field codes did not intrinsically produce a persistent "memory" of attractor states. These models, therefore, were not continuous attractor networks.

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Introducción: La relación entre la corteza entorrinal y el hipocampo ha sido estudiada por diferentes autores, que han destacado la importancia de las células de cuadrícula, las células de posicionamiento y la conexión trisináptica en los procesos que regulan: la persistencia de la memoria espacial, explícita y reciente, y su posible afección con el envejecimiento. Objetivo: Observar si existen diferencias en el tamaño y número de células de cuadrícula contenidas en la lámina iii de la corteza entorrinal y en la capa granular del giro dentado del hipocampo de pacientes mayores. Métodos: Realizamos estudios posmortem del cerebro de 6 sujetos de edades comprendidas entre los 56 y 87 años. Los cortes de cerebros que contenían el giro dentado del hipocampo y la corteza entorrinal adyacente se tiñeron con el método de Klüver-Barrera, después se midió, mediante el programa Image J, el área neuronal individual, el área neuronal total, así como el número de neuronas, contenidas en cuadrículas rectangulares a nivel de la lámina iii de la corteza entorrinal y la lámina ii del giro dentado y se llevó a cabo un análisis estadístico. Resultados: Se ha observado una reducción de la población celular de la capa piramidal externa de la corteza entorrinal, así como de las neuronas de la capa granular del giro dentado relacionada con el envejecimiento. Conclusión: Nuestros resultados indican que el envejecimiento produce una disminución en el tamaño y la densidad neuronal en las células de cuadrícula de la corteza entorrinal y de posicionamiento del giro dentado.(AU)

Introduction: The relationship between the entorhinal cortex and the hippocampus has been studied by different authors, who have highlighted the importance of grid cells, place cells, and the trisynaptic circuit in the processes that they regulate: the persistence of spatial, explicit, and recent memory and their possible impairment with ageing. Objective: We aimed to determine whether older age causes changes in the size and number of grid cells contained in layer III of the entorhinal cortex and in the granular layer of the dentate gyrus of the hippocampus. Methods: We conducted post-mortem studies of the brains of 6 individuals aged 56-87 years. The brain sections containing the dentate gyrus and the adjacent entorhinal cortex were stained according to the Klüver-Barrera method, then the Image J software was used to measure the individual neuronal area, the total neuronal area, and the number of neurons contained in rectangular areas in layer III of the entorhinal cortex and layer II of the dentate gyrus. Statistical analysis was subsequently performed. Results: We observed an age-related reduction in the cell population of the external pyramidal layer of the entorhinal cortex, and in the number of neurons in the granular layer of the dentate gyrus. Conclusion: Our results indicate that ageing causes a decrease in the size and density of grid cells of the entorhinal cortex and place cells of the dentate gyrus.(AU)

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Place cell with location tuning characteristics play an important role in brain spatial cognition and navigation, but there is relatively little research on place cell screening and its influencing factors. Taking pigeons as model animals, the screening process of pigeon place cell was given by using the spike signal in pigeon hippocampus under free activity. The effects of grid number and filter kernel size on the place field of place cells during the screening process were analyzed. The results from the real and simulation data showed that the proposed place cell screening method presented in this study could effectively screen out place cell, and the research found that the size of place field was basically inversely proportional to the number of grids divided, and was basically proportional to the size of Gaussian filter kernel in the overall trend. This result will not only help to determine the appropriate parameters in the place cell screening process, but also promote the research on the neural mechanism of spatial cognition and navigation of birds such as pigeons.

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Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are activated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and coordinate hippocampal replay to guide subsequent spatial navigation.

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The quest to understand the memory engram has intrigued humans for centuries. Recent technological advances, including genetic labelling, imaging, optogenetic and chemogenetic techniques, have propelled the field of memory research forward. These tools have enabled researchers to create and erase memory components. While these innovative techniques have yielded invaluable insights, they often focus on specific elements of the memory trace. Genetic labelling may rely on a particular immediate early gene as a marker of activity, optogenetics may activate or inhibit one specific type of neuron, and imaging may capture activity snapshots in a given brain region at specific times. Yet, memories are multifaceted, involving diverse arrays of neuronal subpopulations, circuits, and regions that work in concert to create, store, and retrieve information. Consideration of contributions of both excitatory and inhibitory neurons, micro and macro circuits across brain regions, the dynamic nature of active ensembles, and representational drift is crucial for a comprehensive understanding of the complex nature of memory.

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Physiological studies have revealed that rats perform spatial localization relying on grid cells and place cells in the entorhinal-hippocampal CA3 structure. The dynamic connection between the entorhinal-hippocampal structure and the prefrontal cortex is crucial for navigation. Based on these findings, this paper proposes a spatial navigation method based on the entorhinal-hippocampal-prefrontal information transmission circuit of the rat's brain, with the aim of endowing the mobile robot with strong spatial navigation capability. Using the hippocampal CA3-prefrontal spatial navigation model as a foundation, this paper constructed a dynamic self-organizing model with the hippocampal CA1 place cells as the basic unit to optimize the navigation path. The path information was then fed back to the impulse neural network via hippocampal CA3 place cells and prefrontal cortex action neurons, improving the convergence speed of the model and helping to establish long-term memory of navigation habits. To verify the validity of the method, two-dimensional simulation experiments and three-dimensional simulation robot experiments were designed in this paper. The experimental results showed that the method presented in this paper not only surpassed other algorithms in terms of navigation efficiency and convergence speed, but also exhibited good adaptability to dynamic navigation tasks. Furthermore, our method can be effectively applied to mobile robots.

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The cognitive map, proposed by Tolman in the 1940s, is a hypothetical internal representation of space constructed by the brain to enable an animal to undertake flexible spatial behaviors such as navigation. The subsequent discovery of place cells in the hippocampus of rats suggested that such a map-like representation does exist, and also provided a tool with which to explore its properties. Single-neuron studies in rodents conducted in small singular spaces have suggested that the map is founded on a metric framework, preserving distances and directions in an abstract representational format. An open question is whether this metric structure pertains over extended, often complexly structured real-world space. The data reviewed here suggest that this is not the case. The emerging picture is that instead of being a single, unified construct, the map is a mosaic of fragments that are heterogeneous, variably metric, multiply scaled, and sometimes laid on top of each other. Important organizing factors within and between fragments include boundaries, context, compass direction, and gravity. The map functions not to provide a comprehensive and precise rendering of the environment but rather to support adaptive behavior, tailored to the species and situation.

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INTRODUCTION: The relationship between the entorhinal cortex (EC) and the hippocampus has been studied by different authors, who have highlighted the importance of grid cells, place cells, and the trisynaptic circuit in the processes that they regulate: the persistence of spatial, explicit, and recent memory and their possible impairment with ageing. OBJECTIVE: We aimed to determine whether older age causes changes in the size and number of grid cells contained in layer III of the EC and in the granular layer of the dentate gyrus (DG) of the hippocampus. METHODS: We conducted post-mortem studies of the brains of 6 individuals aged 56-87 years. The brain sections containing the DG and the adjacent EC were stained according to the Klüver-Barrera method, then the ImageJ software was used to measure the individual neuronal area, the total neuronal area, and the number of neurons contained in rectangular areas in layer III of the EC and layer II of the DG. Statistical analysis was subsequently performed. RESULTS: We observed an age-related reduction in the cell population of the external pyramidal layer of the EC, and in the number of neurons in the granular layer of the DG. CONCLUSION: Our results indicate that ageing causes a decrease in the size and density of grid cells of the EC and place cells of the DG.

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A normative model for the emergence of entorhinal grid cells in the brain's navigational system has been proposed (Sorscher et al., 2023. Neuron 111, 121-137). Using computational modeling of place-to-grid cell interactions, the authors characterized the fundamental nature of grid cells through information processing. However, the normative model does not consider certain discoveries that complement or contradict the conditions for such emergence. By briefly reviewing current evidence, we draw some implications on the interplay between place cell replay sequences and intrinsic grid cell oscillations related to the hippocampal-entorhinal navigation system that can extend the normative model.

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Effective self-localization requires that the brain can resolve ambiguities in incoming sensory information arising from self-similarities (symmetries) in the environment structure. We investigated how place cells use environmental cues to resolve the ambiguity of a rotationally symmetric environment, by recording from hippocampal CA1 in rats exploring a "2-box." This apparatus comprises two adjacent rectangular compartments, identical but with directionally opposed layouts (cue card at one end and central connecting doorway) and distinguished by their odor contexts (lemon vs. vanilla). Despite the structural and visual rotational symmetry of the boxes, no place cells rotated their place fields. The majority changed their firing fields (remapped) between boxes but some repeated them, maintaining a translational symmetry and thus adopting a relationship to the layout that was conditional on the odor. In general, the place field ensemble maintained a stable relationship to environment orientation as defined by the odors, but sometimes the whole ensemble rotated its firing en bloc, decoupling from the odor context cues. While the individual elements of these observations-odor remapping, place field repetition, ensemble rotation, and decoupling from context-have been reported in isolation, the combination in the one experiment is incompletely explained within current models. We redress this by proposing a model in which odor cues enter into a three-way association with layout cues and head direction, creating a configural context signal that facilitates two separate processes: place field orientation and place field positioning. This configuration can subsequently still function in the absence of one of its components, explaining the ensemble decoupling from odor. We speculate that these interactions occur in retrosplenial cortex, because it has previously been implicated in context processing, and all the relevant signals converge here.

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OBJECTIVE: Spatial memory deficits are an early symptom in Alzheimer's disease (AD), reflecting the neurodegenerative processes in the neuronal navigation network such as in hippocampal and parietal cortical areas. As no effective treatment options are available, neuromodulatory interventions are increasingly evaluated. Against this backdrop, we investigated the neuromodulatory effect of anodal transcranial direct current stimulation (tDCS) on hippocampal place learning in patients with AD or mild cognitive impairment (MCI). METHODS: In this randomized, double-blind, sham-controlled study with a cross-over design anodal tDCS of the right temporoparietal junction (2 mA for 20 min) was applied to 20 patients diagnosed with AD or MCI and in 22 healthy controls while they performed a virtual navigation paradigm testing hippocampal place learning. RESULTS: We show an improved recall performance of hippocampal place learning after anodal tDCS in the patient group compared to sham stimulation but not in the control group. CONCLUSIONS: These results suggest that tDCS can facilitate spatial memory consolidation via stimulating the parietal-hippocampal navigation network in AD and MCI patients. SIGNIFICANCE: Our findings suggest that tDCS of the temporoparietal junction may restore spatial navigation and memory deficits in patients with AD and MCI.

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Spatial learning is critical for survival and its underlying neuronal mechanisms have been studied extensively. These studies have revealed a wealth of information about the neural representations of space, such as place cells and boundary cells. While many studies have focused on how these representations emerge in the brain, their functional role in driving spatial learning and navigation has received much less attention. We extended an existing computational modeling tool-chain to study the functional role of spatial representations using closed-loop simulations of spatial learning. At the heart of the model agent was a spiking neural network that formed a ring attractor. This network received inputs from place and boundary cells and the location of the activity bump in this network was the output. This output determined the movement directions of the agent. We found that the navigation performance depended on the parameters of the place cell input, such as their number, the place field sizes, and peak firing rate, as well as, unsurprisingly, the size of the goal zone. The dependence on the place cell parameters could be accounted for by just a single variable, the overlap index, but this dependence was nonmonotonic. By contrast, performance scaled monotonically with the Fisher information of the place cell population. Our results therefore demonstrate that efficiently encoding spatial information is critical for navigation performance.

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Visual virtual reality (VR) systems for head-fixed mice offer advantages over real-world studies for investigating the neural circuitry underlying behavior. However, current VR approaches do not fully cover the visual field of view of mice, do not stereoscopically illuminate the binocular zone, and leave the lab frame visible. To overcome these limitations, we developed iMRSIV (Miniature Rodent Stereo Illumination VR)-VR goggles for mice. Our system is compact, separately illuminates each eye for stereo vision, and provides each eye with an ∼180° field of view, thus excluding the lab frame while accommodating saccades. Mice using iMRSIV while navigating engaged in virtual behaviors more quickly than in a current monitor-based system and displayed freezing and fleeing reactions to overhead looming stimulation. Using iMRSIV with two-photon functional imaging, we found large populations of hippocampal place cells during virtual navigation, global remapping during environment changes, and unique responses of place cell ensembles to overhead looming stimulation.

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Spatial memories are represented by hippocampal place cells during navigation. This spatial code is dynamic, undergoing changes across time, known as representational drift, and across changes in internal state, even while navigating the same spatial environment with consistent behavior. A dynamic code may provide the hippocampus a means to track distinct epochs of experience that occur at different times or during different internal states and update spatial memories. Changes to the spatial code include place fields (PFs) that remap to new locations and place fields that vanish, while others are stable. However, what determines place field fate across epochs remains unclear. We measured the lap-by-lap properties of place cells in mice during navigation for a block of trials in a rewarded virtual environment. We then determined the position of the place fields in another block of trials in the same spatial environment either separated by a day (a distinct temporal epoch) or during the same session but with reward removed to change reward expectation (a distinct internal state epoch). We found that place cells with remapped place fields across epochs tended to have lower spatial precision during navigation in the initial epoch. Place cells with stable or vanished place fields tended to have higher spatial precision. We conclude that place cells with less precise place fields have greater spatial flexibility, allowing them to respond to, and track, distinct epochs of experience in the same spatial environment, while place cells with precise place fields generally preserve spatial information when their fields reappear.

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