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Current Biology : CB Sep 2023Remote memories play an important role in how we perceive the world, and they are rooted throughout the brain in "engrams": ensembles of cells that are formed during...
Remote memories play an important role in how we perceive the world, and they are rooted throughout the brain in "engrams": ensembles of cells that are formed during acquisition. Upon their reactivation, a specific memory can be recalled. Many studies have focused on the ensembles in CA1 of the hippocampus and the anterior cingulate cortex (ACC). However, the evolution of these components during systems' consolidation has not yet been comprehensively addressed. By applying transgenic approaches for ensemble identification, CLARITY, retro-AAV, and pseudo-rabies virus for circuit mapping, and chemogenetics for functional interrogation, we addressed the dynamics of recent and remote CA1 ensembles. We expected both stability (as they represent the same memory) and maturation (over time). Indeed, we found that CA1 engrams remain stable between recent and remote recalls, and the inhibition of engrams for recent recall during remote recall functionally impairs memory. We also found that new cells in the remote recall engram in the CA1 are not added randomly during maturation but differ according to their connections. First, we show in two ways that the anterograde CA1 → ACC engram cell projection grows larger. Finally, in the retrograde projections, the ACC reduces input to CA1 engram cells, whereas input from the entorhinal cortex and paraventricular nucleus of the thalamus increases. Our results shine fresh light on systems' consolidation by providing a deeper understanding of engram stability and maturation in the transition from recent to remote memory.
Topics: Hippocampus; Memory, Long-Term; Mental Recall; Entorhinal Cortex; Gyrus Cinguli
PubMed: 37586373
DOI: 10.1016/j.cub.2023.07.042 -
Neural Networks : the Official Journal... Jul 2022In building artificial intelligence (AI) agents, referring to how brains function in real environments can accelerate development by reducing the design space. In this...
In building artificial intelligence (AI) agents, referring to how brains function in real environments can accelerate development by reducing the design space. In this study, we propose a probabilistic generative model (PGM) for navigation in uncertain environments by integrating the neuroscientific knowledge of hippocampal formation (HF) and the engineering knowledge in robotics and AI, namely, simultaneous localization and mapping (SLAM). We follow the approach of brain reference architecture (BRA) (Yamakawa, 2021) to compose the PGM and outline how to verify the model. To this end, we survey and discuss the relationship between the HF findings and SLAM models. The proposed hippocampal formation-inspired probabilistic generative model (HF-PGM) is designed to be highly consistent with the anatomical structure and functions of the HF. By referencing the brain, we elaborate on the importance of integration of egocentric/allocentric information from the entorhinal cortex to the hippocampus and the use of discrete-event queues.
Topics: Artificial Intelligence; Brain; Entorhinal Cortex; Hippocampus; Robotics
PubMed: 35468492
DOI: 10.1016/j.neunet.2022.04.001 -
Advanced Science (Weinheim,... Aug 2023The hippocampal-entorhinal system supports cognitive function and is selectively vulnerable to Alzheimer's disease (AD). Little is known about global transcriptomic...
The hippocampal-entorhinal system supports cognitive function and is selectively vulnerable to Alzheimer's disease (AD). Little is known about global transcriptomic changes in the hippocampal-entorhinal subfields during AD. Herein, large-scale transcriptomic analysis is performed in five hippocampal-entorhinal subfields of postmortem brain tissues (262 unique samples). Differentially expressed genes are assessed across subfields and disease states, and integrated genotype data from an AD genome-wide association study. An integrative gene network analysis of bulk and single-nucleus RNA sequencing (snRNA-Seq) data identifies genes with causative roles in AD progression. Using a system-biology approach, pathology-specific expression patterns for cell types are demonstrated, notably upregulation of the A1-reactive astrocyte signature in the entorhinal cortex (EC) during AD. SnRNA-Seq data show that PSAP signaling is involved in alterations of cell- communications in the EC during AD. Further experiments validate the key role of PSAP in inducing astrogliosis and an A1-like reactive astrocyte phenotype. In summary, this study reveals subfield-, cell type-, and AD pathology-specific changes and demonstrates PSAP as a potential therapeutic target in AD.
Topics: Humans; Alzheimer Disease; Transcriptome; Genome-Wide Association Study; Hippocampus; Entorhinal Cortex
PubMed: 37232225
DOI: 10.1002/advs.202300876 -
Nature Jan 2024The medial entorhinal cortex (MEC) hosts many of the brain's circuit elements for spatial navigation and episodic memory, operations that require neural activity to be...
The medial entorhinal cortex (MEC) hosts many of the brain's circuit elements for spatial navigation and episodic memory, operations that require neural activity to be organized across long durations of experience. Whereas location is known to be encoded by spatially tuned cell types in this brain region, little is known about how the activity of entorhinal cells is tied together over time at behaviourally relevant time scales, in the second-to-minute regime. Here we show that MEC neuronal activity has the capacity to be organized into ultraslow oscillations, with periods ranging from tens of seconds to minutes. During these oscillations, the activity is further organized into periodic sequences. Oscillatory sequences manifested while mice ran at free pace on a rotating wheel in darkness, with no change in location or running direction and no scheduled rewards. The sequences involved nearly the entire cell population, and transcended epochs of immobility. Similar sequences were not observed in neighbouring parasubiculum or in visual cortex. Ultraslow oscillatory sequences in MEC may have the potential to couple neurons and circuits across extended time scales and serve as a template for new sequence formation during navigation and episodic memory formation.
Topics: Animals; Mice; Entorhinal Cortex; Neurons; Parahippocampal Gyrus; Running; Time Factors; Darkness; Visual Cortex; Periodicity; Neural Pathways; Spatial Navigation; Memory, Episodic
PubMed: 38123682
DOI: 10.1038/s41586-023-06864-1 -
Progress in Neuro-psychopharmacology &... Aug 2023Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting... (Review)
Review
Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting mnemonic trace is referred to as Episodic Memory, i.e. the "what", "where" and "when" of a lived episode. The journey for such memory trace encoding begins with the perceptual data of an experienced episode handled in sensory brain regions. The information is then streamed to cortical areas located in the ventral Medio Temporal Lobe, which produces multi-modal representations concerning either the objects (in the Perirhinal cortex) or the spatial and contextual features (in the parahippocampal region) of the episode. Then, this high-level data is gated through the Entorhinal Cortex and forwarded to the Hippocampal Formation, where all the pieces get bound together. Eventually, the resulting encoded neural pattern is relayed back to the Neocortex for a stable consolidation. This review will detail these different stages and provide a systematic overview of the major cortical streams toward the Hippocampus relevant for Episodic Memory encoding.
Topics: Memory, Episodic; Hippocampus; Entorhinal Cortex; Temporal Lobe; Neural Pathways
PubMed: 37086812
DOI: 10.1016/j.pnpbp.2023.110757 -
Nature Communications Oct 2023Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory...
Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine's impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal's spatial position, as mice navigated virtual reality and real world environments. Ketamine acutely increased firing rates, degraded cell-pair temporal firing-rate relationships, and altered oscillations, leading to longer-term remapping of spatial representations. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings demonstrate ketamine-induced dysfunction of the MEC-hippocampal circuit at the single cell, local-circuit population, and network levels, connecting previously demonstrated physiological effects of ketamine on spatial cognition to alterations in the spatial navigation circuit.
Topics: Mice; Animals; Ketamine; Entorhinal Cortex; Hippocampus; Neurons; Cognition
PubMed: 37805575
DOI: 10.1038/s41467-023-41750-4 -
Cell Reports Feb 2023The claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. Its regional anatomy and cell-type-specific connections...
The claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. Its regional anatomy and cell-type-specific connections in the mouse remain not fully determined. Using multimodal reference datasets, we confirmed the delineation of the mouse CLA as a single group of neurons embedded in the agranular insular cortex. We quantitatively investigated brain-wide inputs and outputs of CLA using bulk anterograde and retrograde viral tracing data and single neuron tracing data. We found that the prefrontal module has more cell types projecting to the CLA than other cortical modules, with layer 5 IT neurons predominating. We found nine morphological types of CLA principal neurons that topographically innervate functionally linked cortical targets, preferentially the midline cortical areas, secondary motor area, and entorhinal area. Together, this study provides a detailed wiring diagram of the cell-type-specific connections of the mouse CLA, laying a foundation for studying its functions at the cellular level.
Topics: Mice; Animals; Claustrum; Neural Pathways; Entorhinal Cortex; Neurons; Motor Cortex
PubMed: 36774552
DOI: 10.1016/j.celrep.2023.112118 -
Proceedings of the National Academy of... Feb 2022The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How...
The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here, we examined the topographic arrangement of spatially modulated neurons in the superficial layers of MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD, and OV cells tended to intermingle. These data suggest that grid cell networks might be largely distinct from those of border, HD, and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types.
Topics: Animals; Brain Mapping; Entorhinal Cortex; Male; Mice; Microscopy; Miniaturization; Motor Activity; Neurons
PubMed: 35135885
DOI: 10.1073/pnas.2121655119 -
Nature Reviews. Neuroscience Oct 2021Entorhinal cortical grid cells fire in a periodic pattern that tiles space, which is suggestive of a spatial coordinate system. However, irregularities in the grid... (Review)
Review
Entorhinal cortical grid cells fire in a periodic pattern that tiles space, which is suggestive of a spatial coordinate system. However, irregularities in the grid pattern as well as responses of grid cells in contexts other than spatial navigation have presented a challenge to existing models of entorhinal function. In this Perspective, we propose that hippocampal input provides a key informative drive to the grid network in both spatial and non-spatial circumstances, particularly around salient events. We build on previous models in which neural activity propagates through the entorhinal-hippocampal network in time. This temporal contiguity in network activity points to temporal order as a necessary characteristic of representations generated by the hippocampal formation. We advocate that interactions in the entorhinal-hippocampal loop build a topological representation that is rooted in the temporal order of experience. In this way, the structure of grid cell firing supports a learned topology rather than a rigid coordinate frame that is bound to measurements of the physical world.
Topics: Animals; Entorhinal Cortex; Grid Cells; Hippocampus; Humans; Learning; Models, Neurological; Nerve Net; Space Perception
PubMed: 34453151
DOI: 10.1038/s41583-021-00499-9 -
Nature Communications Apr 2022Extensive studies concluded that homophilic interactions between pre- and postsynaptic teneurins, evolutionarily conserved cell-adhesion molecules, encode the...
Extensive studies concluded that homophilic interactions between pre- and postsynaptic teneurins, evolutionarily conserved cell-adhesion molecules, encode the specificity of synaptic connections. However, no direct evidence is available to demonstrate that teneurins are actually required on both pre- and postsynaptic neurons for establishing synaptic connections, nor is it known whether teneurins are localized to synapses. Using super-resolution microscopy, we demonstrate that Teneurin-3 assembles into presynaptic nanoclusters of approximately 80 nm in most excitatory synapses of the hippocampus. Presynaptic deletions of Teneurin-3 and Teneurin-4 in the medial entorhinal cortex revealed that they are required for assembly of entorhinal cortex-CA1, entorhinal cortex-subiculum, and entorhinal cortex-dentate gyrus synapses. Postsynaptic deletions of teneurins in the CA1 region, however, had no effect on synaptic connections from any presynaptic input. Our data suggest that different from the current prevailing view, teneurins promote the establishment of synaptic connections exclusively as presynaptic cell-adhesion molecules, most likely via their nanomolar-affinity binding to postsynaptic latrophilins.
Topics: Entorhinal Cortex; Hippocampus; Ligands; Neurons; Synapses
PubMed: 35484136
DOI: 10.1038/s41467-022-29751-1