Entorhinal-hippocampal System Research Articles

Successive POI Recommendation via Brain-Inspired Spatiotemporal Aware Representation

Existing approaches usually perform spatiotemporal representation in the spatial and temporal dimensions, respectively, which isolates the spatial and temporal natures of the target and leads to sub-optimal embeddings. Neuroscience research has shown that the mammalian brain entorhinal-hippocampal system provides efficient graph representations for general knowledge. Moreover, entorhinal grid cells present concise spatial representations, while hippocampal place cells represent perception conjunctions effectively. Thus, the entorhinal-hippocampal system provides a novel angle for spatiotemporal representation, which inspires us to propose the SpatioTemporal aware Embedding framework (STE) and apply it to POIs (STEP). STEP considers two types of POI-specific representations: sequential representation and spatiotemporal conjunctive representation, learned using sparse unlabeled data based on the proposed graph-building policies. Notably, STEP jointly represents the spatiotemporal natures of POIs using both observations and contextual information from integrated spatiotemporal dimensions by constructing a spatiotemporal context graph. Furthermore, we introduce a successive POI recommendation method using STEP, which achieves state-of-the-art performance on two benchmarks. In addition, we demonstrate the excellent performance of the STE representation approach in other spatiotemporal representation-centered tasks through a case study of the traffic flow prediction problem. Therefore, this work provides a novel solution to spatiotemporal representation and paves a new way for spatiotemporal modeling-related tasks.

Somatosensory-Evoked Early Sharp Waves in the Neonatal Rat Hippocampus.

The developing entorhinal-hippocampal system is embedded within a large-scale bottom-up network, where spontaneous myoclonic movements, presumably via somatosensory feedback, trigger hippocampal early sharp waves (eSPWs). The hypothesis, that somatosensory feedback links myoclonic movements with eSPWs, implies that direct somatosensory stimulation should also be capable of evoking eSPWs. In this study, we examined hippocampal responses to electrical stimulation of the somatosensory periphery in urethane-anesthetized, immobilized neonatal rat pups using silicone probe recordings. We found that somatosensory stimulation in ~33% of the trials evoked local field potential (LFP) and multiple unit activity (MUA) responses identical to spontaneous eSPWs. The somatosensory-evoked eSPWs were delayed from the stimulus, on average, by 188 ms. Both spontaneous and somatosensory-evoked eSPWs (i) had similar amplitude of ~0.5 mV and half-duration of ~40 ms, (ii) had similar current-source density (CSD) profiles, with current sinks in CA1 strata radiatum, lacunosum-moleculare and DG molecular layer and (iii) were associated with MUA increase in CA1 and DG. Our results indicate that eSPWs can be triggered by direct somatosensory stimulations and support the hypothesis that sensory feedback from movements is involved in the association of eSPWs with myoclonic movements in neonatal rats.

Optrode recording of an entorhinal-cortical circuit in freely moving mice.

The deep layers of medial entorhinal cortex (MEC) are considered a crucial station for spatial cognition and memory. The deep sublayer Va of MEC (MECVa) serves as the output stage of the entorhinal-hippocampal system and sends extensive projections to brain cortical areas. However, the functional heterogeneity of these efferent neurons in MECVa is poorly understood, due to the difficulty of performing single-neuron activity recording from the narrow band of cell population while the animals are behaving. In the current study, we combined multi-electrode electrophysiological recording and optical stimulation to record cortical-projecting MECVa neurons at single-neuron resolution in freely moving mice. First, injection of a viral Cre-LoxP system was used to express channelrhodopsin-2 specifically in MECVa neurons that project to the medial part of the secondary visual cortex (V2M-projecting MECVa neurons). Then, a lightweight, self-made optrode was implanted into MECVa to identify the V2M-projecting MECVa neurons and to enable single-neuron activity recordings in mice performing the open field test and 8-arm radial maze. Our results demonstrate that optrode approach is an accessible and reliable method for single-neuron recording of V2M-projecting MECVa neurons in freely moving mice, paving the way for future circuit studies designed to characterize the activity of MECVa neurons during specific tasks.

Spatialization of Time in the Entorhinal-Hippocampal System.

The functional role of the entorhinal-hippocampal system has been a long withstanding mystery. One key theory that has become most popular is that the entorhinal-hippocampal system represents space to facilitate navigation in one’s surroundings. In this Perspective article, I introduce a novel idea that undermines the inherent uniqueness of spatial information in favor of time driving entorhinal-hippocampal activity. Specifically, by spatializing events that occur in succession (i.e., across time), the entorhinal-hippocampal system is critical for all types of cognitive representations. I back up this argument with empirical evidence that hints at a role for the entorhinal-hippocampal system in non-spatial representation, and computational models of the logarithmic compression of time in the brain.

Flexible modulation of sequence generation in the entorhinal-hippocampal system.

Exploration, consolidation, and planning depend on the generation of sequential state representations. However, these algorithms require disparate forms of sampling dynamics for optimal performance. We theorize how the brain should adapt internally generated sequences for particular cognitive functions and propose a neural mechanism by which this may be accomplished within the entorhinal-hippocampal circuit. Specifically, we demonstrate that the systematic modulation along the MEC dorsoventral axis of grid population input into hippocampus facilitates a flexible generative process which can interpolate between qualitatively distinct regimes of sequential hippocampal reactivations. By relating the emergent hippocampal activity patterns drawn from our model to empirical data, we explain and reconcile a diversity of recently observed, but apparently unrelated, phenomena such as generative cycling, diffusive hippocampal reactivations, and jumping trajectory events.

A Sensing Framework for Indoor Spatial Awareness for Blind and Visually Impaired Users

In this paper, we present Bluetooth low energy (BLE)-based sensing framework that provides real time spatial awareness for blind and visually impaired (BVI) users while navigating independently through large public venues. The proposed framework includes the following functionalities using only the received signal strength indicator obtained from the BLE sensors: 1) determining the location of the user, 2) estimating the user's moving direction, and 3) detecting the proximity of landmarks next to the user. We evaluate these functionalities individually. Moreover, we incorporate the proposed framework in PERCEPT indoor navigation system and test it with BVI users in a large public venue. Testing results show that the location, moving direction, and landmark proximity computed by the framework, although not very accurate, provide sufficient information to enable BVI users to independently navigate in large indoor venues. This conclusion aligns with Nobel Prize winning findings that confirm the spatial nature of the entorhinal-hippocampal system and the existence of a positioning system in the brain.

Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System.

The basal forebrain cholinergic system (BFCS) robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum, central amygdala, paraventricular nucleus of hypothalamus, dorsal raphe, and parabrachial nucleus. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal–hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function.

The neurodynamic bases of imitating learning and episodic memory

In this review, three essentially important processes in development of cognitive behavior are considered: knowledge of a spatial environment by means of physical activity, coding and a call of an existential context of episodic memory and imitation learning based on the mirror neural mechanism. The data show that the parietal and frontal system of learning by imitation, allows the developing organism to seize skills of management and motive synergies in perisomatic space, to understand intentions and the purposes of observed actions of other individuals. At the same time a widely distributed parietal and frontal and entorhinal-hippocampal system mediates spatial knowledge and the solution of the navigation tasks important for creation of an existential context of episodic memory.

An Entorhinal-Hippocampal Model for Simultaneous Cognitive Map Building

Hippocampal place cells and entorhinal grid cells have been hypothesized to be able to form map-like spatial representation of the environment, namely cognitive map. In most prior approaches, either neural network methods or only hippocampal models are used for building cognitive maps, lacking biological fidelity to the entorhinal-hippocampal system. This paper presents a novel computational model to build cognitive maps of real environments using both place cells and grid cells. The proposed model includes two major components: (1) A competitive Hebbian learning algorithm is used to select velocity-coupled grid cell population activities, which path-integrate self-motion signals to determine computation of place cell population activities; (2) Visual cues of environments are used to correct the accumulative errors intrinsically associated with the path integration process. Experiments performed on a mobile robot show that cognitive maps of the real environment can be efficiently built. The proposed model would provide an alternative neuro-inspired approach for robotic mapping, navigation and localization.

From brain synapses to systems for learning and memory: Object recognition, spatial navigation, timed conditioning, and movement control

This article provides an overview of neural models of synaptic learning and memory whose expression in adaptive behavior depends critically on the circuits and systems in which the synapses are embedded. It reviews Adaptive Resonance Theory, or ART, models that use excitatory matching and match-based learning to achieve fast category learning and whose learned memories are dynamically stabilized by top-down expectations, attentional focusing, and memory search. ART clarifies mechanistic relationships between consciousness, learning, expectation, attention, resonance, and synchrony. ART models are embedded in ARTSCAN architectures that unify processes of invariant object category learning, recognition, spatial and object attention, predictive remapping, and eye movement search, and that clarify how conscious object vision and recognition may fail during perceptual crowding and parietal neglect. The generality of learned categories depends upon a vigilance process that is regulated by acetylcholine via the nucleus basalis. Vigilance can get stuck at too high or too low values, thereby causing learning problems in autism and medial temporal amnesia. Similar synaptic learning laws support qualitatively different behaviors: Invariant object category learning in the inferotemporal cortex; learning of grid cells and place cells in the entorhinal and hippocampal cortices during spatial navigation; and learning of time cells in the entorhinal–hippocampal system during adaptively timed conditioning, including trace conditioning. Spatial and temporal processes through the medial and lateral entorhinal–hippocampal system seem to be carried out with homologous circuit designs. Variations of a shared laminar neocortical circuit design have modeled 3D vision, speech perception, and cognitive working memory and learning. A complementary kind of inhibitory matching and mismatch learning controls movement.This article is part of a Special Issue entitled SI: Brain and Memory.

How does the modular organization of entorhinal grid cells develop?

The entorhinal-hippocampal system plays a crucial role in spatial cognition and navigation. Since the discovery of grid cells in layer II of medial entorhinal cortex (MEC), several types of models have been proposed to explain their development and operation; namely, continuous attractor network models, oscillatory interference models, and self-organizing map (SOM) models. Recent experiments revealing the in vivo intracellular signatures of grid cells (Domnisoru et al., 2013; Schmidt-Heiber and Hausser, 2013), the primarily inhibitory recurrent connectivity of grid cells (Couey et al., 2013; Pastoll et al., 2013), and the topographic organization of grid cells within anatomically overlapping modules of multiple spatial scales along the dorsoventral axis of MEC (Stensola et al., 2012) provide strong constraints and challenges to existing grid cell models. This article provides a computational explanation for how MEC cells can emerge through learning with grid cell properties in modular structures. Within this SOM model, grid cells with different rates of temporal integration learn modular properties with different spatial scales. Model grid cells learn in response to inputs from multiple scales of directionally-selective stripe cells (Krupic et al., 2012; Mhatre et al., 2012) that perform path integration of the linear velocities that are experienced during navigation. Slower rates of grid cell temporal integration support learned associations with stripe cells of larger scales. The explanatory and predictive capabilities of the three types of grid cell models are comparatively analyzed in light of recent data to illustrate how the SOM model overcomes problems that other types of models have not yet handled.

Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation

In this study, we investigated the hypothesis whether neurotrophins have a differential influence on neurite growth from the entorhinal cortex depending on the presence or absence of hippocampal target tissue. We investigated organotypic brain slices derived from the entorhinal-hippocampal system to analyze the effects of endogenous and recombinant neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) on neurite outgrowth and reinnervation. In the reinnervation assay, entorhinal cortex explants of transgenic mice expressing enhanced green fluorescent protein (EGFP) were co-cultured with wild-type hippocampi under the influence of recombinant NT-3 and NT-4 (500 ng/ml). Both recombinant NT-3 and NT-4 significantly increased the growth of EGFP+ nerve fibers into the target tissue. Consistently, reinnervation of the hippocampi of NT-4(-/-) and NT-3(+/-)NT-4(-/-) mice was substantially reduced. In contrast, the outgrowth assay did not exhibit reduction in axon outgrowth of NT-4(-/-) or NT-3(+/-)NT-4(-/-) cortex explants, while the application of recombinant NT-3 (500 ng/ml) induced a significant increase in the neurite extension of cortex explants. Recombinant NT-4 had no effect. In summary, only recombinant NT-3 stimulates axon outgrowth from cortex explants, while both endogenous and recombinant NT-3 and NT-4 synergistically promote reinnervation of the denervated hippocampus. These results suggest that endogenous and exogenous NT-3 and NT-4 differentially influence neurite growth depending on the presence or absence of target tissue.

Entorhinal theta phase precession sculpts dentate gyrus place fields

It is known that the hippocampus facilitates memory formation and spatial representation and that hippocampal place cells establish spatial representations with firing activity modulated in terms of 'theta phase precession'. Clarifying how these spatial and temporal activities interact to process information is essential for a more coherent understanding of the way the hippocampus works. Recently, it has been reported that layer II entorhinal cortical cells, which mediate the majority of the cortical inputs to the dentate gyrus (DG), located at the gate of the hippocampus, fire with theta phase precession according to a grid-like pattern. Here we hypothesize that the temporal code of entorhinal grid neurons firing with theta phase precession provides selectivity in input integration of dentate neurons to support the emergence of place fields. Our large-scale network model analyses demonstrated that, by assuming coincidence detection properties of dentate neurons, grid fields are reliably transformed to place fields in a novel environment. Furthermore, global remapping of place fields in sequential experiences of environments can be obtained in agreement with known experimental observation. These findings indicate a critical role of temporal coding for space computation in the entorhinal-hippocampal system.

Cooperation between the hippocampus and the entorhinal cortex in spatial memory: A disconnection study

It has been recently shown that lesions of parahippocampal areas including the entorhinal cortex do not disrupt place learning in the water maze, suggesting that the hippocampo-cortical circuitry is not important for spatial memory [Burwell RD, Saddoris MP, Bucci DJ, Wiig KA. Corticohippocampal contributions to spatial and contextual learning. J Neurosci 2004;24:3826–36]. The aim of the present study was to tax more directly the cooperation between the hippocampus and entorhinal cortex in two different spatial tasks, a place navigation task and a spontaneous object exploration task, using a disconnection procedure. Damaging the entorhinal–hippocampal system induced impairments in the two tasks but only in the spatial object exploration task rats with contralateral lesions displayed a greater deficit than rats with ipsilateral lesions. The results suggest that the cooperation between the hippocampus and the entorhinal cortex is modulated by the nature of the task and the cognitive processes involved in formation of spatial memory.

Effect of early isolation on the synaptic function in the dentate gyrus and field CA1 of the guinea pig.

We previously reported that neonatal isolation shapes neuron morphology remarkably in the dentate gyrus and hippocampus of the guinea pig, a precocial rodent whose brain is at an advanced stage of maturation at birth. The aim of the present work was to investigate the effects of early isolation on the physiology of the hippocampal trisynaptic circuit. Male and female guinea pigs were assigned at 6-7 days of age to either a social or an isolated environment. After 90-100 days, the animals were anesthetized and electrophysiological experiments were carried out. The monosynaptic response evoked by medial perforant path stimulation in the dentate gyrus (DG) and the following response trisynaptically evoked in field CA1 by the DG-CA3 system were evaluated with several stimulus protocols: (1) current source-density (CSD) analysis; (2) input/output function; (3) paired-pulse potentiation (PPP); and (4) long-term potentiation (LTP). Isolated animals exhibited a reduction in the magnitude of the current sinks in the middle molecular layer and granule cell layer of the DG and in the input/output function of the granule cell population excitatory postsynaptic potential (EPSP) and population spike (PS) over a wide range of stimuli. The latter effect was larger in males. The ratio between the PS and EPSP of the granule cells was reduced in isolated compared to control males, but the opposite occurred in females. Isolation affected PPP of the granule cell response in males only, causing a larger facilitation of the PS. No isolation-related effects were found in the magnitude of the LTP of the DG response in either sex. Isolated animals exhibited a reduction in the current sinks in stratum radiatum and stratum pyramidale of field CA1 and in the input/output function of the EPSP and PS of field CA1. These effects were larger in males. The results show that early isolation causes a reduction in the synaptic function of the DG-CA3-CA1 system, driven by perforant path volleys. The isolation-induced impairment in signal processing along the hippocampal network suggests that the outcome of early isolation may be an impairment in the memory functions in which the entorhinal-hippocampal system plays a key role.

Differential effects of preoperative overtraining on non-matching-to-place performance of rats with entorhinal and hippocampal lesions

In the present study, a novel procedure of non-matching-to-place (NMTP) task in the radial maze was devised and the effects of lesions of the entorhinal cortex and hippocampus on spatially guided working/reference memory were investigated. Both groups of rats with the entorhinal and hippocampal lesions showed severe impairment of performance on the NMTP task at delay of 0 min, whereas sham lesioned rats rapidly reacquired the task. Overtraining of the NMTP task before lesion considerably ameliorated behavioral performance of rats with the entorhinal cortex lesion, although hippocampal lesioned rats showed no improvement of performance. When various delay intervals (0, 1, 3, and 9 min) were randomly interposed between the information run and the choice run in the delayed NMTP test, delay-dependent impairments were shown in the entorhinal lesioned rats which reacquired postoperative NMTP task. These results indicate the possibility of differential effects of overtraining on the entorhinal cortex and hippocampus, in that the entorhinal-hippocampal system is initially involved in both spatially guided working and reference memory, and after overtraining, reference memory as well as spatially guided working memory is left on the function of the hippocampus, but the entorhinal cortex becomes to play a critical role of spatially guided working memory.

Morphological and numerical analysis of synaptic interactions between neurons in deep and superficial layers of the entorhinal cortex of the rat.

Neurons providing connections between the deep and superficial layers of the entorhinal cortex (EC) constitute a pivotal link in the network underlying reverberation and gating of neuronal activity in the entorhinal-hippocampal system. To learn more of these deep-to-superficial neurons and their targets, we applied the tracer Neurobiotin pericellularly in layer V of the medial EC of 12 rats. Labeled axons in the superficial layers were studied with light and electron microscopy, and their synaptic organization recorded. Neurobiotin-labeled layer V neurons displayed "Golgi-like" staining. Two major cell types were distinguished among these neurons: (1) pyramidal neurons with apical spiny dendrites traversing all layers and ramifying in layer I, and (2) horizontal neurons with dendrites confined to the deep layers. Labeled axons ramified profusely in layer III, superficially in layer II and deep in layer I. Analysis of labeled axon terminals in layers I-II and III showed that most synapses (95%) were asymmetrical. Of these synapses, 56% occurred with spines (presumably belonging to principal neurons) and 44% with dendritic shafts (presumably interneurons). A small fraction of the synapses (5%) was of the symmetrical type. Such synapses were mainly seen on dendritic shafts. We found in two sections a symmetrical synapse on a spine. These findings suggest that the deep to superficial projection is mainly excitatory in nature, and that these fibers subserve both excitation and feed-forward inhibition. There is an additional, much weaker, inhibitory component in this projection, which may have a disinhibitory effect on the entorhinal network in the superficial layers.

Entorhinal-hippocampal interactions revealed by real-time imaging.

The entorhinal cortex provides the major cortical input to the hippocampus, and both structures have been implicated in memory processes. The dynamics of neuronal circuits in the entorhinal-hippocampal system were studied in slices by optical imaging with high spatial and temporal resolution. Reverberation of neural activity was detected in the entorhinal cortex and was more prominent when the inhibition due to gamma-aminobutyric acid was slightly suppressed. Neural activity was transferred in a frequency-dependent way from the entorhinal cortex to the hippocampus. The entorhinal neuronal circuit could contribute to memory processes by holding information and selectively gating the entry of information into the hippocampus.

Cellular and subcellular distribution of receptors in the entorhinal—hippocampal system: Morphologic and biochemical aspects

Cellular and subcellular distribution of receptors in the entorhinal—hippocampal system: Morphologic and biochemical aspects

Plasticity in the entorhinal—hippocampal system

Plasticity in the entorhinal—hippocampal system