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1
Naumann, Robert K., Patricia Preston-Ferrer, Michael Brecht, and Andrea Burgalossi. "Structural modularity and grid activity in the medial entorhinal cortex." Journal of Neurophysiology 119, no. 6 (June 1, 2018): 2129–44. http://dx.doi.org/10.1152/jn.00574.2017.
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Following the groundbreaking discovery of grid cells, the medial entorhinal cortex (MEC) has become the focus of intense anatomical, physiological, and computational investigations. Whether and how grid activity maps onto cell types and cortical architecture is still an open question. Fundamental similarities in microcircuits, function, and connectivity suggest a homology between rodent MEC and human posteromedial entorhinal cortex. Both are specialized for spatial processing and display similar cellular organization, consisting of layer 2 pyramidal/calbindin cell patches superimposed on scattered stellate neurons. Recent data indicate the existence of a further nonoverlapping modular system (zinc patches) within the superficial MEC layers. Zinc and calbindin patches have been shown to receive largely segregated inputs from the presubiculum and parasubiculum. Grid cells are also clustered in the MEC, and we discuss possible structure-function schemes on how grid activity could map onto cortical patch systems. We hypothesize that in the superficial layers of the MEC, anatomical location can be predictive of function; thus relating functional properties and neuronal morphologies to the cortical modules will be necessary for resolving how grid activity maps onto cortical architecture. Imaging or cell identification approaches in freely moving animals will be required for testing this hypothesis.
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Deshmukh, Sachin S., D. Yoganarasimha, Horatiu Voicu, and James J. Knierim. "Theta Modulation in the Medial and the Lateral Entorhinal Cortices." Journal of Neurophysiology 104, no. 2 (August 2010): 994–1006. http://dx.doi.org/10.1152/jn.01141.2009.
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Hippocampal neurons show a strong modulation by theta frequency oscillations. This modulation is thought to be important not only for temporal encoding and decoding of information in the hippocampal system, but also for temporal ordering of neuronal activities on timescales at which physiological mechanisms of synaptic plasticity operate. The medial entorhinal cortex (MEC), one of the two major cortical inputs to the hippocampus, is known to show theta modulation. Here, we show that the local field potentials (LFPs) in the other major cortical input to the hippocampus, the lateral entorhinal cortex (LEC), show weaker theta oscillations than those shown in the MEC. Neurons in LEC also show weaker theta modulation than that of neurons in MEC. These findings suggest that LEC inputs are integrated into hippocampal representations in a qualitatively different manner than the MEC inputs. Furthermore, MEC grid cells increase the scale of their periodic spatial firing patterns along the dorsoventral axis, corresponding to the increasing size of place fields along the septotemporal axis of the hippocampus. We show here a corresponding gradient in the tendency of MEC neural firing to skip alternate theta cycles. We propose a simple model based on interference of delta oscillations with theta oscillations to explain this behavior.
3
Wang, Cheng, Xiaojing Chen, Heekyung Lee, Sachin S. Deshmukh, D. Yoganarasimha, Francesco Savelli, and James J. Knierim. "Egocentric coding of external items in the lateral entorhinal cortex." Science 362, no. 6417 (November 22, 2018): 945–49. http://dx.doi.org/10.1126/science.aau4940.
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Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations.
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GUANELLA, ALEXIS, DANIEL KIPER, and PAUL VERSCHURE. "A MODEL OF GRID CELLS BASED ON A TWISTED TORUS TOPOLOGY." International Journal of Neural Systems 17, no. 04 (August 2007): 231–40. http://dx.doi.org/10.1142/s0129065707001093.
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The grid cells of the rat medial entorhinal cortex (MEC) show an increased firing frequency when the position of the animal correlates with multiple regions of the environment that are arranged in regular triangular grids. Here, we describe an artificial neural network based on a twisted torus topology, which allows for the generation of regular triangular grids. The association of the activity of pre-defined hippocampal place cells with entorhinal grid cells allows for a highly robust-to-noise calibration mechanism, suggesting a role for the hippocampal back-projections to the entorhinal cortex.
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Knierim, James J., Joshua P. Neunuebel, and Sachin S. Deshmukh. "Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local–global reference frames." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1635 (February 5, 2014): 20130369. http://dx.doi.org/10.1098/rstb.2013.0369.
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The hippocampus receives its major cortical input from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input. We review new data which suggest that this simple dichotomy between ‘where’ versus ‘what’ needs revision. We propose a refinement of this model, which is more complex than the simple spatial–non-spatial dichotomy. MEC is proposed to be involved in path integration computations based on a global frame of reference, primarily using internally generated, self-motion cues and external input about environmental boundaries and scenes; it provides the hippocampus with a coordinate system that underlies the spatial context of an experience. LEC is proposed to process information about individual items and locations based on a local frame of reference, primarily using external sensory input; it provides the hippocampus with information about the content of an experience.
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Luna, Victor M., Christoph Anacker, Nesha S. Burghardt, Hameda Khandaker, Valentine Andreu, Amira Millette, Paige Leary, et al. "Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus." Science 364, no. 6440 (May 9, 2019): 578–83. http://dx.doi.org/10.1126/science.aat8789.
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Young adult-born granule cells (abGCs) in the dentate gyrus (DG) have a profound impact on cognition and mood. However, it remains unclear how abGCs distinctively contribute to local DG information processing. We found that the actions of abGCs in the DG depend on the origin of incoming afferents. In response to lateral entorhinal cortex (LEC) inputs, abGCs exert monosynaptic inhibition of mature granule cells (mGCs) through group II metabotropic glutamate receptors. By contrast, in response to medial entorhinal cortex (MEC) inputs, abGCs directly excite mGCs throughN-methyl-d-aspartate receptors. Thus, a critical function of abGCs may be to regulate the relative synaptic strengths of LEC-driven contextual information versus MEC-driven spatial information to shape distinct neural representations in the DG.
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Gurgenidze, Shalva, Peter Bäuerle, Dietmar Schmitz, Imre Vida, Tengis Gloveli, and Tamar Dugladze. "Cell-Type Specific Inhibition Controls the High-Frequency Oscillations in the Medial Entorhinal Cortex." International Journal of Molecular Sciences 23, no. 22 (November 15, 2022): 14087. http://dx.doi.org/10.3390/ijms232214087.
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The medial entorhinal cortex (mEC) plays a critical role for spatial navigation and memory. While many studies have investigated the principal neurons within the entorhinal cortex, much less is known about the inhibitory circuitries within this structure. Here, we describe for the first time in the mEC a subset of parvalbumin-positive (PV+) interneurons (INs)—stuttering cells (STUT)—with morphological, intrinsic electrophysiological, and synaptic properties distinct from fast-spiking PV+ INs. In contrast to the fast-spiking PV+ INs, the axon of the STUT INs also terminated in layer 3 and showed subthreshold membrane oscillations at gamma frequencies. Whereas the synaptic output of the STUT INs was only weakly reduced by a μ-opioid agonist, their inhibitory inputs were strongly suppressed. Given these properties, STUT are ideally suited to entrain gamma activity in the pyramidal cell population of the mEC. We propose that activation of the μ-opioid receptors decreases the GABA release from the PV+ INs onto the STUT, resulting in disinhibition of the STUT cell population and the consequent increase in network gamma power. We therefore suggest that the opioid system plays a critical role, mediated by STUT INs, in the neural signaling and oscillatory network activity within the mEC.
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Ye, Jing, Menno P. Witter, May-Britt Moser, and Edvard I. Moser. "Entorhinal fast-spiking speed cells project to the hippocampus." Proceedings of the National Academy of Sciences 115, no. 7 (January 31, 2018): E1627—E1636. http://dx.doi.org/10.1073/pnas.1720855115.
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The mammalian positioning system contains a variety of functionally specialized cells in the medial entorhinal cortex (MEC) and the hippocampus. In order for cells in these systems to dynamically update representations in a way that reflects ongoing movement in the environment, they must be able to read out the current speed of the animal. Speed is encoded by speed-responsive cells in both MEC and hippocampus, but the relationship between the two populations has not been determined. We show here that many entorhinal speed cells are fast-spiking putative GABAergic neurons. Using retrograde viral labeling from the hippocampus, we find that a subset of these fast-spiking MEC speed cells project directly to hippocampal areas. This projection contains parvalbumin (PV) but not somatostatin (SOM)-immunopositive cells. The data point to PV-expressing GABAergic projection neurons in MEC as a source for widespread speed modulation and temporal synchronization in entorhinal–hippocampal circuits for place representation.
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Zhang, Sheng-Jia, Jing Ye, Jonathan J. Couey, Menno Witter, Edvard I. Moser, and May-Britt Moser. "Functional connectivity of the entorhinal–hippocampal space circuit." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1635 (February 5, 2014): 20120516. http://dx.doi.org/10.1098/rstb.2012.0516.
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The mammalian space circuit is known to contain several functionally specialized cell types, such as place cells in the hippocampus and grid cells, head-direction cells and border cells in the medial entorhinal cortex (MEC). The interaction between the entorhinal and hippocampal spatial representations is poorly understood, however. We have developed an optogenetic strategy to identify functionally defined cell types in the MEC that project directly to the hippocampus. By expressing channelrhodopsin-2 (ChR2) selectively in the hippocampus-projecting subset of entorhinal projection neurons, we were able to use light-evoked discharge as an instrument to determine whether specific entorhinal cell groups—such as grid cells, border cells and head-direction cells—have direct hippocampal projections. Photoinduced firing was observed at fixed minimal latencies in all functional cell categories, with grid cells as the most abundant hippocampus-projecting spatial cell type. We discuss how photoexcitation experiments can be used to distinguish the subset of hippocampus-projecting entorhinal neurons from neurons that are activated indirectly through the network. The functional breadth of entorhinal input implied by this analysis opens up the potential for rich dynamic interactions between place cells in the hippocampus and different functional cell types in the entorhinal cortex (EC).
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Campbell, Malcolm G., and Lisa M. Giocomo. "Self-motion processing in visual and entorhinal cortices: inputs, integration, and implications for position coding." Journal of Neurophysiology 120, no. 4 (October 1, 2018): 2091–106. http://dx.doi.org/10.1152/jn.00686.2017.
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The sensory signals generated by self-motion are complex and multimodal, but the ability to integrate these signals into a unified self-motion percept to guide navigation is essential for animal survival. Here, we summarize classic and recent work on self-motion coding in the visual and entorhinal cortices of the rodent brain. We compare motion processing in rodent and primate visual cortices, highlighting the strengths of classic primate work in establishing causal links between neural activity and perception, and discuss the integration of motor and visual signals in rodent visual cortex. We then turn to the medial entorhinal cortex (MEC), where calculations using self-motion to update position estimates are thought to occur. We focus on several key sources of self-motion information to MEC: the medial septum, which provides locomotor speed information; visual cortex, whose input has been increasingly recognized as essential to both position and speed-tuned MEC cells; and the head direction system, which is a major source of directional information for self-motion estimates. These inputs create a large and diverse group of self-motion codes in MEC, and great interest remains in how these self-motion codes might be integrated by MEC grid cells to estimate position. However, which signals are used in these calculations and the mechanisms by which they are integrated remain controversial. We end by proposing future experiments that could further our understanding of the interactions between MEC cells that code for self-motion and position and clarify the relationship between the activity of these cells and spatial perception.
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Fernández-Ruiz, Antonio, Azahara Oliva, Marisol Soula, Florbela Rocha-Almeida, Gergo A. Nagy, Gonzalo Martin-Vazquez, and György Buzsáki. "Gamma rhythm communication between entorhinal cortex and dentate gyrus neuronal assemblies." Science 372, no. 6537 (April 1, 2021): eabf3119. http://dx.doi.org/10.1126/science.abf3119.
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Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.
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Pilly, Praveen K., and Stephen Grossberg. "How Do Spatial Learning and Memory Occur in the Brain? Coordinated Learning of Entorhinal Grid Cells and Hippocampal Place Cells." Journal of Cognitive Neuroscience 24, no. 5 (May 2012): 1031–54. http://dx.doi.org/10.1162/jocn_a_00200.
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Spatial learning and memory are important for navigation and formation of episodic memories. The hippocampus and medial entorhinal cortex (MEC) are key brain areas for spatial learning and memory. Place cells in hippocampus fire whenever an animal is located in a specific region in the environment. Grid cells in the superficial layers of MEC provide inputs to place cells and exhibit remarkable regular hexagonal spatial firing patterns. They also exhibit a gradient of spatial scales along the dorsoventral axis of the MEC, with neighboring cells at a given dorsoventral location having different spatial phases. A neural model shows how a hierarchy of self-organizing maps, each obeying the same laws, responds to realistic rat trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with unimodal firing fields that fit neurophysiological data about their development in juvenile rats. The hippocampal place fields represent much larger spaces than the grid cells to support navigational behaviors. Both the entorhinal and hippocampal self-organizing maps amplify and learn to categorize the most energetic and frequent co-occurrences of their inputs. Top–down attentional mechanisms from hippocampus to MEC help to dynamically stabilize these spatial memories in both the model and neurophysiological data. Spatial learning through MEC to hippocampus occurs in parallel with temporal learning through lateral entorhinal cortex to hippocampus. These homologous spatial and temporal representations illustrate a kind of “neural relativity” that may provide a substrate for episodic learning and memory.
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Reboreda, Antonio, Ramin Raouf, Angel Alonso, and Philippe Séguéla. "Development of Cholinergic Modulation and Graded Persistent Activity in Layer V of Medial Entorhinal Cortex." Journal of Neurophysiology 97, no. 6 (June 2007): 3937–47. http://dx.doi.org/10.1152/jn.01233.2006.
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During muscarinic modulation, principal neurons from layer V of rat medial entorhinal cortex (mEC) respond to repeated applications of a brief stimulus with a graded change in persistent firing frequency. This pattern of discharge has been proposed to represent an intrinsic mechanism for short-term memory operations. To investigate the implementation of persistent activity in mEC during development, we characterized the electrophysiological properties of layer V principal neurons in the mEC over a range of postnatal stages. We observed significant differences in both passive (resistance, time constant, and resting membrane potential) and active properties (threshold, action potential, and adaptation) of principal neurons from rats aged 5–7, 10–13, 16–19, and 21–23 days. We also examined the properties of muscarinic-dependent persistent activity in EC slices from different age groups. Recordings were conducted using the perforated-patch whole cell technique because persistent activity runs down in the ruptured-patch configuration. Although no neuron in the youngest group exhibited graded persistent activity in response to muscarinic receptor activation, this activity was recorded in the 10- to 13-day-old group and its occurrence increased from 69% in the 16- to 19-day-old group to 76% in the 21- to 23-day-old group. This postnatal increase in neurons endowed with persistent firing properties in mEC was found to parallel the increase in density of ChAT-positive immunostaining of fibers and the developmental changes in M1 muscarinic receptor mRNA levels. All these data suggest that the implementation of mnemonic properties in mEC principal neurons matches the ontogenic development of afferent cholinergic circuits and their signaling components.
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Fukawa, Ayako, Takahiro Aizawa, Hiroshi Yamakawa, and Ikuko Eguchi Yairi. "Identifying Core Regions for Path Integration on Medial Entorhinal Cortex of Hippocampal Formation." Brain Sciences 10, no. 1 (January 5, 2020): 28. http://dx.doi.org/10.3390/brainsci10010028.
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Path integration is one of the functions that support the self-localization ability of animals. Path integration outputs position information after an animal’s movement when initial-position and movement information is input. The core region responsible for this function has been identified as the medial entorhinal cortex (MEC), which is part of the hippocampal formation that constitutes the limbic system. However, a more specific core region has not yet been identified. This research aims to clarify the detailed structure at the cell-firing level in the core region responsible for path integration from fragmentarily accumulated experimental and theoretical findings by reviewing 77 papers. This research draws a novel diagram that describes the MEC, the hippocampus, and their surrounding regions by focusing on the MEC’s input/output (I/O) information. The diagram was created by summarizing the results of exhaustively scrutinizing the papers that are relative to the I/O relationship, the connection relationship, and cell position and firing pattern. From additional investigations, we show function information related to path integration, such as I/O information and the relationship between multiple functions. Furthermore, we constructed an algorithmic hypothesis on I/O information and path-integration calculation method from the diagram and the information of functions related to path integration. The algorithmic hypothesis is composed of regions related to path integration, the I/O relations between them, the calculation performed there, and the information representations (cell-firing pattern) in them. Results of examining the hypothesis confirmed that the core region responsible for path integration was either stellate cells in layer II or pyramidal cells in layer III of the MEC.
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East, Brett S., Lauren R. Brady, and Jennifer J. Quinn. "Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories." Brain Sciences 12, no. 1 (December 28, 2021): 34. http://dx.doi.org/10.3390/brainsci12010034.
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The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.
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Kuruvilla, Maneesh V., David I. G. Wilson, and James A. Ainge. "Lateral entorhinal cortex lesions impair both egocentric and allocentric object–place associations." Brain and Neuroscience Advances 4 (January 2020): 239821282093946. http://dx.doi.org/10.1177/2398212820939463.
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During navigation, landmark processing is critical either for generating an allocentric-based cognitive map or in facilitating egocentric-based strategies. Increasing evidence from manipulation and single-unit recording studies has highlighted the role of the entorhinal cortex in processing landmarks. In particular, the lateral (LEC) and medial (MEC) sub-regions of the entorhinal cortex have been shown to attend to proximal and distal landmarks, respectively. Recent studies have identified a further dissociation in cue processing between the LEC and MEC based on spatial frames of reference. Neurons in the LEC preferentially encode egocentric cues while those in the MEC encode allocentric cues. In this study, we assessed the impact of disrupting the LEC on landmark-based spatial memory in both egocentric and allocentric reference frames. Animals that received excitotoxic lesions of the LEC were significantly impaired, relative to controls, on both egocentric and allocentric versions of an object–place association task. Notably, LEC lesioned animals performed at chance on the egocentric version but above chance on the allocentric version. There was no significant difference in performance between the two groups on an object recognition and spatial T-maze task. Taken together, these results indicate that the LEC plays a role in feature integration more broadly and in specifically processing spatial information within an egocentric reference frame.
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Lepperød, Mikkel Elle, Ane Charlotte Christensen, Kristian Kinden Lensjø, Alessio Paolo Buccino, Jai Yu, Marianne Fyhn, and Torkel Hafting. "Optogenetic pacing of medial septum parvalbumin-positive cells disrupts temporal but not spatial firing in grid cells." Science Advances 7, no. 19 (May 2021): eabd5684. http://dx.doi.org/10.1126/sciadv.abd5684.
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Grid cells in the medial entorhinal cortex (MEC) exhibit remarkable spatial activity patterns with spikes coordinated by theta oscillations driven by the medial septal area (MSA). Spikes from grid cells progress relative to the theta phase in a phenomenon called phase precession, which is suggested as essential to create the spatial periodicity of grid cells. Here, we show that optogenetic activation of parvalbumin-positive (PV+) cells in the MSA enabled selective pacing of local field potential (LFP) oscillations in MEC. During optogenetic stimulation, the grid cells were locked to the imposed pacing frequency but kept their spatial patterns. Phase precession was abolished, and speed information was no longer reflected in the LFP oscillations but was still carried by rate coding of individual MEC neurons. Together, these results support that theta oscillations are not critical to the spatial pattern of grid cells and do not carry a crucial velocity signal.
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Ormond, Jake, and Bruce L. McNaughton. "Place field expansion after focal MEC inactivations is consistent with loss of Fourier components and path integrator gain reduction." Proceedings of the National Academy of Sciences 112, no. 13 (March 2, 2015): 4116–21. http://dx.doi.org/10.1073/pnas.1421963112.
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Both hippocampal place fields and medial entorhinal cortex (MEC) grid fields increase in scale along the dorsoventral axis. Because the connections from MEC to hippocampus are topographically organized and divergent, it has been hypothesized that place fields are generated by a Fourier-like summation of inputs over a range of spatial scales. This hypothesis predicts that inactivation of dorsal MEC should cause place field expansion, whereas inactivation of ventral MEC should cause field contraction. Inactivation of dorsal MEC caused substantial expansion of place fields; however, as inactivations were made more ventrally, the effect diminished but never switched to contraction. Expansion was accompanied by proportional decreases in theta power, intrinsic oscillation frequencies, phase precession slopes, and firing rates. Our results are most consistent with the predicted loss of specific Fourier components coupled with a path integration gain reduction, which raises the overall place field scale and masks the contraction expected from ventral inactivations.
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Hargus, Nicholas J., Aradhya Nigam, Edward H. Bertram, and Manoj K. Patel. "Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis." Journal of Neurophysiology 110, no. 5 (September 1, 2013): 1144–57. http://dx.doi.org/10.1152/jn.00383.2013.
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During epileptogenesis a series of molecular and cellular events occur, culminating in an increase in neuronal excitability, leading to seizure initiation. The entorhinal cortex has been implicated in the generation of epileptic seizures in both humans and animal models of temporal lobe epilepsy. This hyperexcitability is due, in part, to proexcitatory changes in ion channel activity. Sodium channels play an important role in controlling neuronal excitability, and alterations in their activity could facilitate seizure initiation. We sought to investigate whether medial entorhinal cortex (mEC) layer II neurons become hyperexcitable and display proexcitatory behavior of Na channels during epileptogenesis. Experiments were conducted 7 days after electrical induction of status epilepticus (SE), a time point during the latent period of epileptogenesis and before the onset of seizures. mEC layer II stellate neurons from post-SE animals were hyperexcitable, eliciting action potentials at higher frequencies compared with control neurons. Na channel currents recorded from post-SE neurons revealed increases in Na current amplitudes, particularly persistent and resurgent currents, as well as depolarized shifts in inactivation parameters. Immunocytochemical studies revealed increases in voltage-gated Na (Nav) 1.6 isoform levels. The toxin 4,9-anhydro-tetrodotoxin, which has greater selectivity for Nav1.6 over other Na channel isoforms, suppressed neuronal hyperexcitability, reduced macroscopic Na currents, persistent and resurgent Na current densities, and abolished depolarized shifts in inactivation parameters in post-SE neurons. These studies support a potential role for Nav1.6 in facilitating the hyperexcitability of mEC layer II neurons during epileptogenesis.
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Morgan, Nicola H., Ian M. Stanford, and Gavin L. Woodhall. "Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex." Neural Plasticity 2008 (2008): 1–12. http://dx.doi.org/10.1155/2008/808564.
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Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs) at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M), an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC) neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM), increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.
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Feng, Jia, Wen-Hsin Hsu, Denis Patterson, Ching-San Tseng, Hsiang-Wei Hsing, Zi-Hui Zhuang, Yi-Ting Huang, et al. "COUP-TFI specifies the medial entorhinal cortex identity and induces differential cell adhesion to determine the integrity of its boundary with neocortex." Science Advances 7, no. 27 (July 2021): eabf6808. http://dx.doi.org/10.1126/sciadv.abf6808.
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Development of cortical regions with precise, sharp, and regular boundaries is essential for physiological function. However, little is known of the mechanisms ensuring these features. Here, we show that determination of the boundary between neocortex and medial entorhinal cortex (MEC), two abutting cortical regions generated from the same progenitor lineage, relies on COUP-TFI (chicken ovalbumin upstream promoter–transcription factor I), a patterning transcription factor with graded expression in cortical progenitors. In contrast with the classical paradigm, we found that increased COUP-TFI expression expands MEC, creating protrusions and disconnected ectopic tissue. We further developed a mathematical model that predicts that neuronal specification and differential cell affinity contribute to the emergence of an instability region and boundary sharpness. Correspondingly, we demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. Thus, we conclude that a sharp boundary requires a subtle interplay between patterning transcription factors and differential cell affinity.
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Haas, Julie S., and John A. White. "Frequency Selectivity of Layer II Stellate Cells in the Medial Entorhinal Cortex." Journal of Neurophysiology 88, no. 5 (November 1, 2002): 2422–29. http://dx.doi.org/10.1152/jn.00598.2002.
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Electrophysiologically, stellate cells (SCs) from layer II of the medial entorhinal cortex (MEC) are distinguished by intrinsic 4- to 12-Hz subthreshold oscillations. These oscillations are thought to impose a pattern of slow periodic firing that may contribute to the parahippocampal theta rhythm in vivo. Using stimuli with systematically differing frequency content, we examined supra- and subthreshold responses in SCs with the goal of understanding how their distinctive characteristics shape these responses. In reaction to repeated presentations of identical, pseudo-random stimuli, the reliability (repeatability) of the spiking response in SCs depends critically on the frequency content of the stimulus. Reliability is optimal for stimuli with a greater proportion of power in the 4- to 12-Hz range. The simplest mechanistic explanation of these results is that rhythmogenic subthreshold membrane mechanisms resonate with inputs containing significant power in the 4- to 12-Hz band, leading to larger subthreshold excursions and thus enhanced reliability. However, close examination of responses rules out this explanation: SCs do show clear subthreshold resonance (i.e., selective amplification of inputs with particular frequency content) in response to sinusoidal stimuli, while simultaneously showing a lack of subthreshold resonance in response to the pseudo-random stimuli used in reliability experiments. Our results support a model with distinctive input-output relationships under subthreshold and suprathreshold conditions. For suprathreshold stimuli, SC spiking seems to best reflect the amount of input power in the theta (4–12 Hz) frequency band. For subthreshold stimuli, we hypothesize that the magnitude of subthreshold theta-range oscillations in SCs reflects the total power, across all frequencies, of the input.
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Savelli, Francesco, and James J. Knierim. "Hebbian Analysis of the Transformation of Medial Entorhinal Grid-Cell Inputs to Hippocampal Place Fields." Journal of Neurophysiology 103, no. 6 (June 2010): 3167–83. http://dx.doi.org/10.1152/jn.00932.2009.
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The discovery of grid cells in the medial entorhinal cortex (MEC) permits the characterization of hippocampal computation in much greater detail than previously possible. The present study addresses how an integrate-and-fire unit driven by grid-cell spike trains may transform the multipeaked, spatial firing pattern of grid cells into the single-peaked activity that is typical of hippocampal place cells. Previous studies have shown that in the absence of network interactions, this transformation can succeed only if the place cell receives inputs from grids with overlapping vertices at the location of the place cell's firing field. In our simulations, the selection of these inputs was accomplished by fast Hebbian plasticity alone. The resulting nonlinear process was acutely sensitive to small input variations. Simulations differing only in the exact spike timing of grid cells produced different field locations for the same place cells. Place fields became concentrated in areas that correlated with the initial trajectory of the animal; the introduction of feedback inhibitory cells reduced this bias. These results suggest distinct roles for plasticity of the perforant path synapses and for competition via feedback inhibition in the formation of place fields in a novel environment. Furthermore, they imply that variability in MEC spiking patterns or in the rat's trajectory is sufficient for generating a distinct population code in a novel environment and suggest that recalling this code in a familiar environment involves additional inputs and/or a different mode of operation of the network.
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Via, Guillem, Roman Baravalle, Fernando R. Fernandez, John A. White, and Carmen C. Canavier. "Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition." PLOS Computational Biology 18, no. 12 (December 1, 2022): e1010094. http://dx.doi.org/10.1371/journal.pcbi.1010094.
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Theta and gamma oscillations in the hippocampus have been hypothesized to play a role in the encoding and retrieval of memories. Recently, it was shown that an intrinsic fast gamma mechanism in medial entorhinal cortex can be recruited by optogenetic stimulation at theta frequencies, which can persist with fast excitatory synaptic transmission blocked, suggesting a contribution of interneuronal network gamma (ING). We calibrated the passive and active properties of a 100-neuron model network to capture the range of passive properties and frequency/current relationships of experimentally recorded PV+ neurons in the medial entorhinal cortex (mEC). The strength and probabilities of chemical and electrical synapses were also calibrated using paired recordings, as were the kinetics and short-term depression (STD) of the chemical synapses. Gap junctions that contribute a noticeable fraction of the input resistance were required for synchrony with hyperpolarizing inhibition; these networks exhibited theta-nested high frequency oscillations similar to the putative ING observed experimentally in the optogenetically-driven PV-ChR2 mice. With STD included in the model, the network desynchronized at frequencies above ~200 Hz, so for sufficiently strong drive, fast oscillations were only observed before the peak of the theta. Because hyperpolarizing synapses provide a synchronizing drive that contributes to robustness in the presence of heterogeneity, synchronization decreases as the hyperpolarizing inhibition becomes weaker. In contrast, networks with shunting inhibition required non-physiological levels of gap junctions to synchronize using conduction delays within the measured range.
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Brecht, Michael, Saikat Ray, Andrea Burgalossi, Qiusong Tang, Helene Schmidt, and Robert Naumann. "An isomorphic mapping hypothesis of the grid representation." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1635 (February 5, 2014): 20120521. http://dx.doi.org/10.1098/rstb.2012.0521.
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We introduce a grid cell microcircuit hypothesis. We propose the ‘grid in the world’ (evident in grid cell discharges) is generated by a ‘grid in the cortex’. This cortical grid is formed by patches of calbindin-positive pyramidal neurons in layer 2 of medial entorhinal cortex (MEC). Our isomorphic mapping hypothesis assumes three types of isomorphism: (i) metric correspondence of neural space (the two-dimensional cortical sheet) and the external two-dimensional space within patches; (ii) isomorphism between cellular connectivity matrix and firing field; (iii) isomorphism between single cell and population activity. Each patch is a grid cell lattice arranged in a two-dimensional map of space with a neural : external scale of approximately 1 : 2000 in the dorsal part of rat MEC. The lattice behaves like an excitable medium with neighbouring grid cells exciting each other. Spatial scale is implemented as an intrinsic scaling factor for neural propagation speed. This factor varies along the dorsoventral cortical axis. A connectivity scheme of the grid system is described. Head direction input specifies the direction of activity propagation. We extend the theory to neurons between grid patches and predict a rare discharge pattern (inverted grid cells) and the relative location and proportion of grid cells and spatial band cells.
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White, John A., Ruby Klink, Angel Alonso, and Alan R. Kay. "Noise From Voltage-Gated Ion Channels May Influence Neuronal Dynamics in the Entorhinal Cortex." Journal of Neurophysiology 80, no. 1 (July 1, 1998): 262–69. http://dx.doi.org/10.1152/jn.1998.80.1.262.
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White, John A., Ruby Klink, Angel Alonso, and Alan R. Kay. Noise from voltage-gated ion channels may influence neuronal dynamics in the entorhinal cortex. J. Neurophysiol. 80: 262–269, 1998. Neurons of the superficial medial entorhinal cortex (MEC), which deliver neocortical input to the hippocampus, exhibit intrinsic, subthreshold oscillations with slow dynamics. These intrinsic oscillations, driven by a persistent Na+ current and a slow outward current, may help to generate the theta rhythm, a slow rhythm that plays an important role in spatial and declarative learning. Here we show that the number of persistent Na+ channels underlying subthreshold oscillations is relatively small (<104) and use a physiologically based stochastic model to argue that the random behavior of these channels may contribute crucially to cellular-level responses. In acutely isolated MEC neurons under voltage clamp, the mean and variance of the persistent Na+ current were used to estimate the single channel conductance and voltage-dependent probability of opening. A hybrid stochastic-deterministic model was built by using voltage-clamp descriptions of the persistent and fast-inactivating Na+ conductances, along with the fast and slow K+ conductances. All voltage-dependent conductances were represented with nonlinear ordinary differential equations, with the exception of the persistent Na+ conductance, which was represented as a population of stochastic ion channels. The model predicts that the probabilistic nature of Na+ channels increases the cell's repertoire of qualitative behaviors; although deterministic models at a particular point in parameter space can generate either subthreshold oscillations or phase-locked spikes (but rarely both), models with an appropriate level of channel noise can replicate physiological behavior by generating both patterns of electrical activity for a single set of parameters. Channel noise may contribute to higher order interspike interval statistics seen in vitro with DC current stimulation. Models with channel noise show evidence of spike clustering seen in brain slice experiments, although the effect is apparently not as prominent as seen in experimental results. Channel noise may contribute to cellular responses in vivo as well; the stochastic system has enhanced sensitivity to small periodic stimuli in a form of stochastic resonance that is novel (in that the relevant noise source is intrinsic and voltage-dependent) and potentially physiologically relevant. Although based on a simple model that does not include all known membrane mechanisms of MEC stellate cells, these results nevertheless imply that the stochastic nature of small collections of molecules may have important effects at the cellular and network levels.
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Zhang, Jingliang, Xiaoling Chen, Matti Kårbø, Yi Zhao, Long An, Rutao Wang, KeWei Wang, and Zhuo Huang. "Anticonvulsant effect of dipropofol by enhancing native GABA currents in cortical neurons in mice." Journal of Neurophysiology 120, no. 3 (September 1, 2018): 1404–14. http://dx.doi.org/10.1152/jn.00241.2018.
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Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as a short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABAA currents of mEC layer II stellate neurons in a dose-dependent manner with an EC50 value of 9.3 ± 1.6 μM (mean ± SE). Taken together, our findings show that dipropofol activated GABAA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy. NEW & NOTEWORTHY The anticonvulsant effect of dipropofol was shown in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices showed suppression of cortical neuronal excitability by dipropofol. Dipropofol activated the native tonic GABAA currents in a dose-dependent manner.
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Alonso, A., and R. Klink. "Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II." Journal of Neurophysiology 70, no. 1 (July 1, 1993): 128–43. http://dx.doi.org/10.1152/jn.1993.70.1.128.
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1. The electroresponsive properties of neurons from layer II of the rat medial entorhinal cortex (MEC) were studied by intracellular recording under current clamp in an in vitro brain slice preparation. From a total of 184 cells that fulfilled our criteria for recording stability, two groups of projection neurons were distinguished on the basis of their intrinsic biophysical properties and morphological characteristics (demonstrated by intracellular biocytin injection; n = 34). 2. Stellate cells (SCs) were the most abundant (69%). They were highly electroresponsive, and minimal changes (1-3 mV) of membrane potential generated an active response. Subthreshold depolarizing or hyperpolarizing current pulse injection always caused the membrane potential to attain an early peak and then sag to a lower level. Depolarization-induced "sags" were larger and determined early firing in all cells. The voltage-current relationship of SCs was markedly non-linear, demonstrating robust inward rectification in the hyperpolarizing and depolarizing range. 3. SCs generated persistent rhythmic subthreshold voltage oscillations on DC depolarization positive to -60 mV. The mean frequency of the oscillations was 8.6 Hz (theta range) at a membrane potential of approximately -55 mV, at which level occasional single spiking also occurred. At slightly more positive potentials, a striking 1- to 3-Hz repetitive bursting pattern emerged. This consisted of nonadapting trains of spikes ("clusters") interspersed with subthreshold oscillations that had a mean frequency of 21.7 Hz (beta range). 4. Nonstellate cells (39%; mostly pyramidal-like) displayed time-dependent inward rectification that was less pronounced than that of SCs, and minimal depolarization-induced sags. On threshold depolarization, firing was always preceded by a slowly rising ramp depolarization and thus occurred with a long delay. Inward rectification in the depolarizing range was very pronounced. However, non-SCs did not generate persistent rhythmic subthreshold oscillatory activity or spike clusters. 5. Of the electrophysiological parameters quantified, spike threshold, spike duration, depolarizing afterpotential amplitude and apparent membrane time constant demonstrated statistically significant differences between SCs and non-SCs. 6. The repetitive hiring properties in response to square current pulses of short duration (< 500 ms) were also different between SCs and non-SCs. First, most SCs displayed a bilinear frequency-current (f-I) relationship for only the first interspike interval, whereas most non-SCs displayed a bilinear relationship for all intervals. Second, SCs had a much steeper primary f-I slope for early intervals than non-SCs. Finally, SCs displayed more pronounced and faster spike frequency adaptation than non-SCs.(ABSTRACT TRUNCATED AT 400 WORDS)
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Mittal, Divyansh, and Rishikesh Narayanan. "Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations, and intrinsic excitability of entorhinal stellate cells." Journal of Neurophysiology 120, no. 2 (August 1, 2018): 576–600. http://dx.doi.org/10.1152/jn.00136.2018.
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Biological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in channel properties, the impact of such heterogeneities on the robustness of their cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning nine voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 in vitro electrophysiological characteristics of LII stellate cells (SCs). We generated 150,000 models and found a heterogeneous subpopulation of 449 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma-band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale-efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function. NEW & NOTEWORTHY We assessed the impact of heterogeneities in channel properties on the robustness of cellular-scale physiology of medial entorhinal cortical stellate neurons. We demonstrate that neuronal models with disparate channel combinations were endowed with similar physiological characteristics, as a consequence of the many-to-many mapping between channel properties and the physiological characteristics that they modulate. We predict that the spike-triggered average of stellate cells should be endowed with theta-frequency spectral selectivity and fast gamma-band coincidence detection capabilities.
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Smith, Misty D., Gerald W. Saunders, Rasmus P. Clausen, Bente Frǿlund, Povl Krogsgaard-Larsen, Orla M. Larsson, Arne Schousboe, Karen S. Wilcox, and H. Steve White. "Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC)." Epilepsy Research 79, no. 1 (March 2008): 6–13. http://dx.doi.org/10.1016/j.eplepsyres.2007.12.009.
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Carriero, Giovanni, Laura Uva, Vadym Gnatkovsky, Massimo Avoli, and Marco de Curtis. "Independent Epileptiform Discharge Patterns in the Olfactory and Limbic Areas of the In Vitro Isolated Guinea Pig Brain During 4-Aminopyridine Treatment." Journal of Neurophysiology 103, no. 5 (May 2010): 2728–36. http://dx.doi.org/10.1152/jn.00862.2009.
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In vitro studies performed on brain slices demonstrate that the potassium channel blocker 4-aminopyridine (4AP, 50 μM) discloses electrographic seizure activity and interictal discharges. These epileptiform patterns have been further analyzed here in a isolated whole guinea pig brain in vitro by using field potential recordings in olfactory and limbic structures. In 8 of 13 experiments runs of fast oscillatory activity ( fast runs, FRs) in the piriform cortex (PC) propagated to the lateral entorhinal cortex (EC), hippocampus and occasionally to the medial EC. Early and late FRs were asynchronous in the hemispheres showed different duration [1.78 ± 0.51 and 27.95 ± 4.55 (SD) s, respectively], frequency of occurrence (1.82 ± 0.49 and 34.16 ± 6.03 s) and frequency content (20–40 vs. 40–60 Hz). Preictal spikes independent from the FRs appeared in the hippocampus/EC and developed into ictal-like discharges that did not propagate to the PC. Ictal-like activity consisted of fast activity with onset either in the hippocampus ( n = 6) or in the mEC ( n = 2), followed by irregular spiking and sequences of diffusely synchronous bursts. Perfusion of the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid (100 μM) did not prevent FRs, increased the duration of limbic ictal-like discharges and favored their propagation to olfactory structures. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (50 μM) blocked ictal-like events and reduced FRs. In conclusion, 4AP-induced epileptiform activities are asynchronous and independent in olfactory and hippocampal-entorhinal regions. Epileptiform discharges in the isolated guinea pig brain show different pharmacological properties compared with rodent in vitro slices.
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Schwartz, David M., and O. Ozan Koyluoglu. "On the Organization of Grid and Place Cells: Neural Denoising via Subspace Learning." Neural Computation 31, no. 8 (August 2019): 1519–50. http://dx.doi.org/10.1162/neco_a_01208.
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Place cells in the hippocampus (HC) are active when an animal visits a certain location (referred to as a place field) within an environment. Grid cells in the medial entorhinal cortex (MEC) respond at multiple locations, with firing fields that form a periodic and hexagonal tiling of the environment. The joint activity of grid and place cell populations, as a function of location, forms a neural code for space. In this article, we develop an understanding of the relationships between coding theoretically relevant properties of the combined activity of these populations and how these properties limit the robustness of this representation to noise-induced interference. These relationships are revisited by measuring the performances of biologically realizable algorithms implemented by networks of place and grid cell populations, as well as constraint neurons, which perform denoising operations. Contributions of this work include the investigation of coding theoretic limitations of the mammalian neural code for location and how communication between grid and place cell networks may improve the accuracy of each population's representation. Simulations demonstrate that denoising mechanisms analyzed here can significantly improve the fidelity of this neural representation of space. Furthermore, patterns observed in connectivity of each population of simulated cells predict that anti-Hebbian learning drives decreases in inter-HC-MEC connectivity along the dorsoventral axis.
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Langer Horvat, Lea, Ena Španić Popovački, Mirjana Babić Leko, Klara Zubčić, Luka Horvat, Maja Mustapić, Patrick R. Hof, and Goran Šimić. "Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model." Biomedicines 11, no. 4 (March 24, 2023): 1004. http://dx.doi.org/10.3390/biomedicines11041004.
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The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD.
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Yokose, Jun, William D. Marks, Naoki Yamamoto, Sachie K. Ogawa, and Takashi Kitamura. "Entorhinal cortical Island cells regulate temporal association learning with long trace period." Learning & Memory 28, no. 9 (August 16, 2021): 319–28. http://dx.doi.org/10.1101/lm.052589.120.
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Temporal association learning (TAL) allows for the linkage of distinct, nonsynchronous events across a period of time. This function is driven by neural interactions in the entorhinal cortical–hippocampal network, especially the neural input from the pyramidal cells in layer III of medial entorhinal cortex (MECIII) to hippocampal CA1 is crucial for TAL. Successful TAL depends on the strength of event stimuli and the duration of the temporal gap between events. Whereas it has been demonstrated that the neural input from pyramidal cells in layer II of MEC, referred to as Island cells, to inhibitory neurons in dorsal hippocampal CA1 controls TAL when the strength of event stimuli is weak, it remains unknown whether Island cells regulate TAL with long trace periods as well. To understand the role of Island cells in regulating the duration of the learnable trace period in TAL, we used Pavlovian trace fear conditioning (TFC) with a 60-sec long trace period (long trace fear conditioning [L-TFC]) coupled with optogenetic and chemogenetic neural activity manipulations as well as cell type-specific neural ablation. We found that ablation of Island cells in MECII partially increases L-TFC performance. Chemogenetic manipulation of Island cells causes differential effectiveness in Island cell activity and leads to a circuit imbalance that disrupts L-TFC. However, optogenetic terminal inhibition of Island cell input to dorsal hippocampal CA1 during the temporal association period allows for long trace intervals to be learned in TFC. These results demonstrate that Island cells have a critical role in regulating the duration of time bridgeable between associated events in TAL.
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Pilli, Jyotsna, Saad Abbasi, Max Richardson, and Sanjay S. Kumar. "Diversity and excitability of deep-layer entorhinal cortical neurons in a model of temporal lobe epilepsy." Journal of Neurophysiology 108, no. 6 (September 15, 2012): 1724–38. http://dx.doi.org/10.1152/jn.00364.2012.
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The entorhinal cortex (ERC) is critically implicated in temporal lobe epileptogenesis—the most common type of adult epilepsy. Previous studies have suggested that epileptiform discharges likely initiate in seizure-sensitive deep layers (V–VI) of the medial entorhinal area (MEA) and propagate into seizure-resistant superficial layers (II–III) and hippocampus, establishing a lamina-specific distinction between activities of deep- versus superficial-layer neurons and their seizure susceptibilities. While layer II stellate cells in MEA have been shown to be hyperexcitable and hypersynchronous in patients and animal models of temporal lobe epilepsy (TLE), the fate of neurons in the deep layers under epileptic conditions and their overall contribution to epileptogenicity of this region have remained unclear. We used whole cell recordings from slices of the ERC in normal and pilocarpine-treated epileptic rats to characterize the electrophysiological properties of neurons in this region and directly assess changes in their excitatory and inhibitory synaptic drive under epileptic conditions. We found a surprising heterogeneity with at least three major types and two subtypes of functionally distinct excitatory neurons. However, contrary to expectation, none of the major neuron types characterized showed any significant changes in their excitability, barring loss of excitatory and inhibitory inputs in a subtype of neurons whose dendrite extended into layer III, where neurons are preferentially lost during TLE. We confirmed hyperexcitability of layer II neurons in the same slices, suggesting minimal influence of deep-layer input on superficial-layer neuron excitability under epileptic conditions. These data show that deep layers of ERC contain a more diverse population of excitatory neurons than previously envisaged that appear to belie their seizure-sensitive reputation.
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Airapetov, M. I., S. O. Eresko, E. R. Bychkov, A. A. Lebedev, and P. D. Shabanov. "Expression of Toll-like receptors in emotiogenic structures of rat brain is changed under longterm alcohol consumption and ethanol withdrawal." Medical Immunology (Russia) 22, no. 1 (January 31, 2020): 77–86. http://dx.doi.org/10.15789/1563-0625-eot-1836.
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Recent studies have provided strong evidence that long-term ethanol consumption leads to activation the mechanisms of neuroimmune signaling. Recently, much attention has been focused on the study of toll-like receptors (Toll-like receptors, TLRs), which play one of the key roles in the mechanisms of activation of the innate immune system in brain structures subsequently ethanol consumption. It is known that the activation of TLRs leads to the release of many proinflammatory cytokines with the resulting neuroinflammatory process. There are suggestions that TLRs may also be involved in the modulation of neurotransmitter systems of the brain, thereby contributing to the formation of pathological dependence on ethanol. The goal of our work was to study the level of expression the genes of TLRs (TLR3, TLR4, TLR7) and pro-inflammatory cytokine genes (IL-1β, CCL2) in the rat brain (amygdala, hippocampus, medial entorhinal cortex, striatum) under conditions of prolonged alcoholization and on different periods of alcohol withdrawal, which was previously not studied by researchers. Prolonged alcoholization of rats with ethanol did not lead to changes in levels mRNA of TLRs in the studied structures of the rat brain, with the exception of a small increase in the level of TLR3 mRNA in the hippocampus of prolonged alcoholized rats and a slight increase in the level of TLR3 mRNA in mEC. However, gene expression of TLRs undergoes changes in all the structures of the rat brain studied by us at different periods of alcohol withdrawal. The increased level of expression of both TLRs and proinflammatory genes in the period of alcohol withdrawal in the rat brain hippocampus deserves special attention, which indicates the presence of a persistent neuroinflammatory process in this brain structure in the period of alcohol withdrawal, which is probably supported with the participation of TLR-dependent signaling. The study of the mechanisms of inflammatory process activation by TLR-dependent signaling in different brain structures can open new targets for drug exposure. Such drugs can be used in the treatment of alcoholism.
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Biella, Gerardo, and Marco de Curtis. "Olfactory Inputs Activate the Medial Entorhinal Cortex Via the Hippocampus." Journal of Neurophysiology 83, no. 4 (April 1, 2000): 1924–31. http://dx.doi.org/10.1152/jn.2000.83.4.1924.
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The lateral and medial regions of the entorhinal cortex differ substantially in terms of connectivity and pattern of activation. With regard to olfactory input, a detailed and extensive physiological map of the olfactory projection to the entorhinal cortex is missing, even if anatomic studies suggest that the olfactory afferents are confined to the lateral and rostral entorhinal region. We studied the contribution of the medial and lateral entorhinal areas to olfactory processing by analyzing the responses induced by lateral olfactory tract stimulation in different entorhinal subfields of the in vitro isolated guinea pig brain. The pattern of synaptic activation of the medial and lateral entorhinal regions was reconstructed either by performing simultaneous multisite recordings or by applying current source density analysis on field potential laminar profiles obtained with 16-channel silicon probes. Current source density analysis demonstrated the existence of a direct monosynaptic olfactory input into the superficial 300 μm of the most rostral part of the lateral entorhinal cortex exclusively, whereas disynaptic sinks mediated by associative fibers arising from the piriform cortex were observed at 100–350 μm depth in the entire lateral aspect of the cortex. No local field responses were recorded in the medial entorhinal region unless a large population spike was generated in the hippocampus (dentate gyrus and CA1 region) by a stimulus 3–5× the intensity necessary to obtain a maximal monosynaptic response in the piriform cortex. In these conditions, a late sink was recorded at a depth of 600-1000 μm in the medial entorhinal area (layers III–V) 10.6 ± 0.9 (SD) msec after a population spike was simultaneously recorded in CA1. Diffuse activation of the medial entorhinal region was also obtained by repetitive low-intensity stimulation of the lateral olfactory tract at 2–8 Hz. Higher or lower stimulation frequencies did not induce hippocampal-medial entorhinal cortex activation. These results suggest that the medial and the lateral entorhinal regions have substantially different roles in processing olfactory sensory inputs.
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Jacob, Pierre-Yves, Tiffany Van Cauter, Bruno Poucet, Francesca Sargolini, and Etienne Save. "Medial entorhinal cortex lesions induce degradation of CA1 place cell firing stability when self-motion information is used." Brain and Neuroscience Advances 4 (January 2020): 239821282095300. http://dx.doi.org/10.1177/2398212820953004.
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The entorhinal–hippocampus network plays a central role in navigation and episodic memory formation. To investigate these interactions, we examined the effect of medial entorhinal cortex lesions on hippocampal place cell activity. Since the medial entorhinal cortex is suggested to play a role in the processing of self-motion information, we hypothesised that such processing would be necessary for maintaining stable place fields in the absence of environmental cues. Place cells were recorded as medial entorhinal cortex–lesioned rats explored a circular arena during five 16-min sessions comprising a baseline session with all sensory inputs available followed by four sessions during which environmental (i.e. visual, olfactory, tactile) cues were progressively reduced to the point that animals could rely exclusively on self-motion cues to maintain stable place fields. We found that place field stability and a number of place cell firing properties were affected by medial entorhinal cortex lesions in the baseline session. When rats were forced to rely exclusively on self-motion cues, within-session place field stability was dramatically decreased in medial entorhinal cortex rats relative to SHAM rats. These results support a major role of the medial entorhinal cortex in processing self-motion cues, with this information being conveyed to the hippocampus to help anchor and maintain a stable spatial representation during movement.
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van der Linden, Solange, Ferruccio Panzica, and Marco de Curtis. "Carbachol Induces Fast Oscillations in the Medial but not in the Lateral Entorhinal Cortex of the Isolated Guinea Pig Brain." Journal of Neurophysiology 82, no. 5 (November 1, 1999): 2441–50. http://dx.doi.org/10.1152/jn.1999.82.5.2441.
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Fast oscillations at 25–80 Hz (gamma activity) have been proposed to play a role in attention-related mechanisms and synaptic plasticity in cortical structures. Recently, it has been demonstrated that the preservation of the entorhinal cortex is necessary to maintain gamma oscillations in the hippocampus. Because gamma activity can be reproduced in vitro by cholinergic activation, this study examined the characteristics of gamma oscillations induced by arterial perfusion or local intracortical injections of carbachol in the entorhinal cortex of the in vitro isolated guinea pig brain preparation. Shortly after carbachol administration, fast oscillatory activity at 25.2–28.2 Hz was observed in the medial but not in the lateral entorhinal cortex. Such activity was transiently associated with oscillations in the theta range that showed a variable pattern of distribution in the entorhinal cortex. No oscillatory activity was observed when carbachol was injected in the lateral entorhinal cortex. Gamma activity in the medial entorhinal cortex showed a phase reversal at 200–400 μm, had maximal amplitude at 400–500 μm depth, and was abolished by arterial perfusion of atropine (5 μM). Local carbachol application in the medial entorhinal cortex induced gamma oscillations in the hippocampus, whereas no oscillations were observed in the amygdala and in the piriform, periamygdaloid, and perirhinal cortices ipsilateral and contralateral to the carbachol injection. Hippocampal oscillations had higher frequency than the gamma activity recorded in the entorhinal cortex, suggesting the presence of independent generators in the two structures. The selective ability of the medial but not the lateral entorhinal cortex to generate gamma activity in response to cholinergic activation suggests a differential mode of signal processing in entorhinal cortex subregions.
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Chapman, C. Andrew, and Ronald J. Racine. "Converging Inputs to the Entorhinal Cortex From the Piriform Cortex and Medial Septum: Facilitation and Current Source Density Analysis." Journal of Neurophysiology 78, no. 5 (November 1, 1997): 2602–15. http://dx.doi.org/10.1152/jn.1997.78.5.2602.
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Chapman, C. Andrew and Ronald J. Racine. Converging inputs to the entorhinal cortex from the piriform cortex and medial septum: facilitation and current source density analysis. J. Neurophysiol. 78: 2602–2615, 1997. The entorhinal cortex receives sensory inputs from the piriform cortex and modulatory inputs from the medial septum. To examine short-term synaptic facilitation effects in these pathways, current source density (CSD) analysis was used first to localize the entorhinal cortex membrane currents, which generate field potentials evoked by stimulation of these afferents. Field potentials were recorded at 50-μm intervals through the medial entorhinal cortex in urethan-anesthetized rats and the one-dimensional CSD was calculated. Piriform cortex stimulation evoked a surface-negative, deep-positive field potential component in the entorhinal cortex with mean onset and peak latencies of 10.4 and 18.4 ms. The component followed brief 100-Hz stimulation, consistent with a monosynaptic response. CSD analysis linked the component to a current sink, which often began in layer I before peaking in layer II. A later, surface-positive field potential component peaked at latencies near 45 ms and was associated with a current source in layer II. Medial septal stimulation evoked positive and negative field potential components which peaked at latencies near 7 and 16 ms, respectively. A weaker and more prolonged surface-negative, deep-positive component peaked at latencies near 25 ms. The early components were generated by currents in the hippocampal formation, and the late surface-negative component was generated by currents in layers II to IV of the entorhinal cortex. Short-term facilitation effects in conscious animals were examined using electrodes chronically implanted near layer II of the entorhinal cortex. Paired-pulse stimulation of the piriform cortex at interpulse intervals of 30 and 40 ms caused the largest facilitation (248%) of responses evoked by the second pulse. Responses evoked by medial septal stimulation also were facilitated maximally (59%) by a piriform cortex conditioning pulse delivered 30–40 ms earlier. Paired pulse stimulation of the medial septum caused the largest facilitation (149%) at intervals of 70 ms, but piriform cortex evoked responses were facilitated maximally (46%) by a septal conditioning pulse 100–200 ms earlier. Frequency potentiation effects were maximal during 12- to 18-Hz stimulation of either the piriform cortex or medial septum. Occlusion tests suggested that piriform cortex and medial septal efferents activate the same neurons. The CSD analysis results show that evoked field potential methods can be used effectively in chronically prepared animals to examine synaptic responses in the converging inputs from the piriform cortex and medial septum to the entorhinal cortex. The short-term potentiation phenomena observed here suggest that low-frequency activity in these pathways during endogenous oscillatory states may enhance entorhinal cortex responsivity to olfactory inputs.
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Dupret, David, and Jozsef Csicsvari. "The medial entorhinal cortex keeps Up." Nature Neuroscience 15, no. 11 (October 26, 2012): 1471–72. http://dx.doi.org/10.1038/nn.3245.
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Lipton, P. A., and H. Eichenbaum. "Complementary Roles of Hippocampus and Medial Entorhinal Cortex in Episodic Memory." Neural Plasticity 2008 (2008): 1–8. http://dx.doi.org/10.1155/2008/258467.
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Spatial mapping and navigation are figured prominently in the extant literature that describes hippocampal function. The medial entorhinal cortex is likewise attracting increasing interest, insofar as evidence accumulates that this area also contributes to spatial information processing. Here, we discuss recent electrophysiological findings that offer an alternate view of hippocampal and medial entorhinal function. These findings suggest complementary contributions of the hippocampus and medial entorhinal cortex in support of episodic memory, wherein hippocampal networks encode sequences of events that compose temporally and spatially extended episodes, whereas medial entorhinal networks disambiguate overlapping episodes by binding sequential events into distinct memories.
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Schmidt, Helene, Anjali Gour, Jakob Straehle, Kevin M. Boergens, Michael Brecht, and Moritz Helmstaedter. "Axonal synapse sorting in medial entorhinal cortex." Nature 549, no. 7673 (September 2017): 469–75. http://dx.doi.org/10.1038/nature24005.
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Kropff, Emilio, James E. Carmichael, May-Britt Moser, and Edvard I. Moser. "Speed cells in the medial entorhinal cortex." Nature 523, no. 7561 (July 2015): 419–24. http://dx.doi.org/10.1038/nature14622.
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Schmidt-Hieber, Christoph, and Michael Häusser. "How to build a grid cell." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1635 (February 5, 2014): 20120520. http://dx.doi.org/10.1098/rstb.2012.0520.
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Neurons in the medial entorhinal cortex fire action potentials at regular spatial intervals, creating a striking grid-like pattern of spike rates spanning the whole environment of a navigating animal. This remarkable spatial code may represent a neural map for path integration. Recent advances using patch-clamp recordings from entorhinal cortex neurons in vitro and in vivo have revealed how the microcircuitry in the medial entorhinal cortex may contribute to grid cell firing patterns, and how grid cells may transform synaptic inputs into spike output during firing field crossings. These new findings provide key insights into the ingredients necessary to build a grid cell.
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Hasselmo, Michael E. "Neuronal rebound spiking, resonance frequency and theta cycle skipping may contribute to grid cell firing in medial entorhinal cortex." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1635 (February 5, 2014): 20120523. http://dx.doi.org/10.1098/rstb.2012.0523.
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Data show a relationship of cellular resonance and network oscillations in the entorhinal cortex to the spatial periodicity of grid cells. This paper presents a model that simulates the resonance and rebound spiking properties of entorhinal neurons to generate spatial periodicity dependent upon phasic input from medial septum. The model shows that a difference in spatial periodicity can result from a difference in neuronal resonance frequency that replicates data from several experiments. The model also demonstrates a functional role for the phenomenon of theta cycle skipping in the medial entorhinal cortex.
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Canto, Cathrin B., and Menno P. Witter. "Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex." Hippocampus 22, no. 6 (December 7, 2011): 1277–99. http://dx.doi.org/10.1002/hipo.20993.
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Høydal, Øyvind Arne, Emilie Ranheim Skytøen, Sebastian Ola Andersson, May-Britt Moser, and Edvard I. Moser. "Object-vector coding in the medial entorhinal cortex." Nature 568, no. 7752 (April 2019): 400–404. http://dx.doi.org/10.1038/s41586-019-1077-7.
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Hinman, James R., Mark P. Brandon, Jason R. Climer, G. William Chapman, and Michael E. Hasselmo. "Multiple Running Speed Signals in Medial Entorhinal Cortex." Neuron 91, no. 3 (August 2016): 666–79. http://dx.doi.org/10.1016/j.neuron.2016.06.027.
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Diehl, Geoffrey W., Olivia J. Hon, Stefan Leutgeb, and Jill K. Leutgeb. "Stability of medial entorhinal cortex representations over time." Hippocampus 29, no. 3 (September 2, 2018): 284–302. http://dx.doi.org/10.1002/hipo.23017.
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