Variaciones de las células de cuadrícula y de posicionamiento de la corteza entorrinal y del giro dentado de 6 humanos de 56 a 87 años / Variations of the grid and place cells in the entorhinal cortex and dentate gyrus of 6 individuals aged 56 to 87 years

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)

Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning.

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.

Mystery of the memory engram: History, current knowledge, and unanswered questions.

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.

[Spatial navigation method based on the entorhinal-hippocampal-prefrontal information transmission circuit of rat's brain].

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.

The mosaic structure of the mammalian cognitive map.

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.

A configural context signal simultaneously but separably drives positioning and orientation of hippocampal place fields.

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.

The grid-cell normative model: Unifying 'principles'.

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.

Transcranial direct current stimulation of the right temporoparietal junction facilitates hippocampal spatial learning in Alzheimer's disease and mild cognitive impairment.

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.

Full field-of-view virtual reality goggles for mice.

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.

The Precision of Place Fields Governs Their Fate across Epochs of Experience.

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.

Flexible coding of time or distance in hippocampal cells.

Analysis of neuronal activity in the hippocampus of behaving animals has revealed cells acting as 'Time Cells', which exhibit selective spiking patterns at specific time intervals since a triggering event, and 'Distance Cells', which encode the traversal of specific distances. Other neurons exhibit a combination of these features, alongside place selectivity. This study aims to investigate how the task performed by animals during recording sessions influences the formation of these representations. We analyzed data from a treadmill running study conducted by Kraus et al., 2013, in which rats were trained to run at different velocities. The rats were recorded in two trial contexts: a 'fixed time' condition, where the animal ran on the treadmill for a predetermined duration before proceeding, and a 'fixed distance' condition, where the animal ran a specific distance on the treadmill. Our findings indicate that the type of experimental condition significantly influenced the encoding of hippocampal cells. Specifically, distance-encoding cells dominated in fixed-distance experiments, whereas time-encoding cells dominated in fixed-time experiments. These results underscore the flexible coding capabilities of the hippocampus, which are shaped by over-representation of salient variables associated with reward conditions.

Unique potential of immature adult-born neurons for the remodeling of CA3 spatial maps.

Mammalian hippocampal circuits undergo extensive remodeling through adult neurogenesis. While this process has been widely studied, the specific contribution of adult-born granule cells (aGCs) to spatial operations in the hippocampus remains unknown. Here, we show that optogenetic activation of 4-week-old (young) aGCs in free-foraging mice produces a non-reversible reconfiguration of spatial maps in proximal CA3 while rarely evoking neural activity. Stimulation of the same neuronal cohort on subsequent days recruits CA3 neurons with increased efficacy but fails to induce further remapping. In contrast, stimulation of 8-week-old (mature) aGCs can reliably activate CA3 cells but produces no alterations in spatial maps. Our results reveal a unique role of young aGCs in remodeling CA3 representations, a potential that can be depleted and is lost with maturation. This ability could contribute to generate orthogonalized downstream codes supporting pattern separation.

Bidirectional synaptic changes in deep and superficial hippocampal neurons following in vivo activity.

Neuronal activity during experience is thought to induce plastic changes within the hippocampal network that underlie memory formation, although the extent and details of such changes in vivo remain unclear. Here, we employed a temporally precise marker of neuronal activity, CaMPARI2, to label active CA1 hippocampal neurons in vivo, followed by immediate acute slice preparation and electrophysiological quantification of synaptic properties. Recently active neurons in the superficial sublayer of stratum pyramidale displayed larger post-synaptic responses at excitatory synapses from area CA3, with no change in pre-synaptic release probability. In contrast, in vivo activity correlated with weaker pre- and post-synaptic excitatory weights onto pyramidal cells in the deep sublayer. In vivo activity of deep and superficial neurons within sharp-wave/ripples was bidirectionally changed across experience, consistent with the observed changes in synaptic weights. These findings reveal novel, fundamental mechanisms through which the hippocampal network is modified by experience to store information.

Multiple long-range projections convey position information to the agranular retrosplenial cortex.

Neuronal signals encoding the animal's position widely modulate neocortical processing. While these signals are assumed to depend on hippocampal output, their origin has not been investigated directly. Here, we asked which brain region sends position information to the retrosplenial cortex (RSC), a key circuit for memory and navigation. We comprehensively characterized the long-range inputs to agranular RSC using two-photon axonal imaging in head-fixed mice performing a spatial task in darkness. Surprisingly, most long-range pathways convey position information, but with notable differences. Axons from the secondary motor and posterior parietal cortex transmit the most position information. By contrast, axons from the anterior cingulate and orbitofrontal cortex and thalamus convey substantially less position information. Axons from the primary and secondary visual cortex contribute negligibly. This demonstrates that the hippocampus is not the only source of position information. Instead, the RSC is a hub in a distributed brain network that shares position information.

A Navigation Path Search and Optimization Method for Mobile Robots Based on the Rat Brain's Cognitive Mechanism.

Rats possess exceptional navigational abilities, allowing them to adaptively adjust their navigation paths based on the environmental structure. This remarkable ability is attributed to the interactions and regulatory mechanisms among various spatial cells within the rat's brain. Based on these, this paper proposes a navigation path search and optimization method for mobile robots based on the rat brain's cognitive mechanism. The aim is to enhance the navigation efficiency of mobile robots. The mechanism of this method is based on developing a navigation habit. Firstly, the robot explores the environment to search for the navigation goal. Then, with the assistance of boundary vector cells, the greedy strategy is used to guide the robot in generating a locally optimal path. Once the navigation path is generated, a dynamic self-organizing model based on the hippocampal CA1 place cells is constructed to further optimize the navigation path. To validate the effectiveness of the method, this paper designs several 2D simulation experiments and 3D robot simulation experiments, and compares the proposed method with various algorithms. The experimental results demonstrate that the proposed method not only surpasses other algorithms in terms of path planning efficiency but also yields the shortest navigation path. Moreover, the method exhibits good adaptability to dynamic navigation tasks.

Representations of tactile object location in the retrosplenial cortex.

How animals use tactile sensation to detect important objects and remember their location in a world-based coordinate system is unclear. Here, we hypothesized that the retrosplenial cortex (RSC), a key network for contextual memory and spatial navigation, represents the location of objects based on tactile sensation. We studied mice palpating objects with their whiskers while navigating in a tactile virtual reality in darkness. Using two-photon Ca2+ imaging, we discovered that a population of neurons in the agranular RSC signal the location of objects. Responses to objects do not simply reflect the sensory stimulus. Instead, they are highly position, task, and context dependent and often predict the upcoming object before it is within reach. In addition, a large fraction of neurons encoding object location maintain a memory trace of the object's location. These data show that the RSC encodes the location and arrangement of tactile objects in a spatial reference frame.

Theta-band phase locking during encoding leads to coordinated entorhinal-hippocampal replay.

Precisely timed interactions between hippocampal and cortical neurons during replay epochs are thought to support learning. Indeed, research has shown that replay is associated with heightened hippocampal-cortical synchrony. Yet many caveats remain in our understanding. Namely, it remains unclear how this offline synchrony comes about, whether it is specific to particular behavioral states, and how-if at all-it relates to learning. In this study, we sought to address these questions by analyzing coordination between CA1 cells and neurons of the deep layers of the medial entorhinal cortex (dMEC) while rats learned a novel spatial task. During movement, we found a subset of dMEC cells that were particularly locked to hippocampal LFP theta-band oscillations and that were preferentially coordinated with hippocampal replay during offline periods. Further, dMEC synchrony with CA1 replay peaked ∼10 ms after replay initiation in CA1, suggesting that the distributed replay reflects extra-hippocampal information propagation and is specific to "offline" periods. Finally, theta-modulated dMEC cells showed a striking experience-dependent increase in synchronization with hippocampal replay trajectories, mirroring the animals' acquisition of the novel task and coupling to the hippocampal local field. Together, these findings provide strong support for the hypothesis that synergistic hippocampal-cortical replay supports learning and highlights phase locking to hippocampal theta oscillations as a potential mechanism by which such cross-structural synchrony comes about.

Awake hippocampal synchronous events are incorporated into offline neuronal reactivation.

Learning novel experiences reorganizes hippocampal neuronal circuits, represented as coordinated reactivation patterns in post-experience offline states for memory consolidation. This study examines how awake synchronous events during a novel run are related to post-run reactivation patterns. The disruption of awake sharp-wave ripples inhibited experience-induced increases in the contributions of neurons to post-experience synchronous events. Hippocampal place cells that participate more in awake synchronous events are more strongly reactivated during post-experience synchronous events. Awake synchronous neuronal patterns, in cooperation with place-selective firing patterns, determine cell ensembles that undergo pronounced increases and decreases in their correlated spikes. Taken together, awake synchronous events are fundamental for identifying hippocampal neuronal ensembles to be incorporated into synchronous reactivation during subsequent offline states, thereby facilitating memory consolidation.

Variations of the grid and place cells in the entorhinal cortex and dentate gyrus of 6 individuals aged 56 to 87 years.

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.