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Menno P Witter - One of the best experts on this subject based on the ideXlab platform.
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the entorhinal cortex of the monkey vi organization of projections from the hippocampus Subiculum preSubiculum and paraSubiculum
The Journal of Comparative Neurology, 2021Co-Authors: Menno P Witter, David G AmaralAbstract:The organization of projections from the macaque monkey hippocampus, Subiculum, preSubiculum, and paraSubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the Subiculum, preSubiculum, and paraSubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the Subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial-to-lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in Subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The preSubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the paraSubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the Subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.
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Connections of the Subiculum of the rat: Topography in relation to columnar and laminar organization
Behavioural brain research, 2006Co-Authors: Menno P WitterAbstract:This paper summarizes published as well as yet unpublished data on the organization of the Subiculum. Because of the complex three-dimensional structure of the hippocampus, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis; particular focus therefore is on data using the so-called extended preparation. On the basis of our yet fragmented insights in the intrinsic network, as well as the known organization of major efferents and afferents, we propose that the Subiculum is organized as a matrix of columnar modules along the transverse axis showing partial laminar connectivity. Although many pieces of the large-scale puzzle on the subicular neuronal network as part of an input-output network for the hippocampus are still missing, it appears that subicular organization is different from that known for CA1. This indicates that major functional differences between CA1 and the Subiculum are to be expected.
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reciprocal connections between the entorhinal cortex and hippocampal fields ca1 and the Subiculum are in register with the projections from ca1 to the Subiculum
Hippocampus, 2001Co-Authors: P A Naber, F Lopes H Da Silva, Menno P WitterAbstract:The topology of the connections between the entorhinal cortex (EC), area CA1, and the Subiculum is characterized by selective and restricted origin and termination along the transverse or proximodistal axis of CA1 and the Subiculum. In the present study, we analyzed whether neurons in CA1 and the Subiculum that receive EC projections are interconnected and give rise to return projections to EC, such that they terminate deep in the area of origin of the EC-to-CA1/Subiculum projections. Both for the lateral and medial subdivision of EC, the projections to CA1/Subiculum, as well as the projections from CA1 to the Subiculum and back to EC, are rather divergent. Interestingly, we only rarely observed evidence for the presence of "reentry loops," i.e., cells in layer III of EC giving rise to projections to interconnected neurons in CA1 and the Subiculum, while the targeted CA1 neurons also projected back to the deep layers of the area of origin of the pathway in EC. We conclude that although fibers originating from a restricted part of EC distribute extensively in a divergent way along the longitudinal axis of CA1 and the Subiculum, only restricted portions of the latter two areas, receiving inputs from the same entorhinal area, are interconnected. Moreover, only a small percentage of the CA1 neurons that project to the correspondingly innervated subicular neurons give rise to projections that return to the deep layers of the originating part of EC. The present findings are taken to indicate that the EC-hippocampal circuitry functionally comprises many parallel-organized specific "reentry loops."
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subicular efferents are organized mostly as parallel projections a double labeling retrograde tracing study in the rat
The Journal of Comparative Neurology, 1998Co-Authors: P A Naber, Menno P WitterAbstract:To understand the functional relevance of the Subiculum as a major distributor of hippocampally processed information, detailed information about its neuronal organization is necessary. A striking feature of the Subiculum is that it can be divided into four different areas, each characterized by a specific set of efferent connections. To establish whether the different areas of the Subiculum are similar with respect to the organization of the origin of their respective efferents, the double-fluorescence retrograde-tracing technique was used to study the degree of collateralization. Because CA1 gives rise to a major input to the Subiculum but also projects to some of the targets reached by subicular projections, we compared the subicular degree of collateralization with that of CA1. Throughout CA1, the percentages of double-labeled cells were high, ranging from 17% to 39%. In contrast, the percentages of double-labeled cells in the Subiculum were much lower, ranging from 0% to 12%, and no differences were noted between the four areas of the Subiculum. This indicates that the four regions of the Subiculum are organized in the same way with regard to the output connectivity. Because all four different regions of the Subiculum share this paucity of collateralized projections, we conclude that subicular outputs generally originate as parallel projections. This characteristic organization is in line with a proposed function of the Subiculum in information storage. J. Comp. Neurol. 393:284–297, 1998. © 1998 Wiley-Liss, Inc.
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projections from the nucleus reuniens thalami to the entorhinal cortex hippocampal field ca1 and the Subiculum in the rat arise from different populations of neurons
The Journal of Comparative Neurology, 1996Co-Authors: M Dollemanvan Der J Weel, Menno P WitterAbstract:The entorhinal cortex, CA1, and the Subiculum receive a major input from the thalamic midline nucleus reuniens. At present, it is not known whether reuniens projections to these intimately interconnected regions are collateralized or arise from different cell populations. We employed the multiple fluorescent retrograde tracing technique with Fast Blue, Diamidino Yellow, and Fluoro-Gold to examine the possible collateralization of reuniens projections to the entorhinal cortex, CA1, and the Subiculum. In addition, we studied the extent of collateralization within each target area. The results indicate that different, yet morphologically indistinguishable, populations of reuniens cells selectively innervate the entorhinal cortex, CA1, or Subiculum. Within each of these areas, reuniens fibers display a locally restricted collateralization instead of distributing collaterals throughout the entire target structure. The rostal two-thirds of the nucleus reuniens is the major source of ipsilateral projections to CA1, Subiculum, and entorhinal cortex. The perireuniens nucleus selectively projects to the perirhinal cortex. Reuniens projections to CA1 and medial entorhinal cortex originate in the dorsolateral part and throughout the medial one-half of the nucleus, respectively. For these two projections, no topography could be established. However, subicular afferents are topographically organized such that a dorsal-to-ventral gradient in the nucleus reuniens corresponds to a dorsal-to-ventral gradient along the subicular axis. Lateral entorhinal afferents display a subtle topography such that a lateral-to-medial shift of terminal fields in the lateral entorhinal cortex corresponds to a lateral-to-medial shift of projection neurons in the ventral nucleus reuniens.
Shane M Omara - One of the best experts on this subject based on the ideXlab platform.
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anterior thalamic inputs are required for Subiculum spatial coding with associated consequences for hippocampal spatial memory
The Journal of Neuroscience, 2021Co-Authors: Bethany E Frost, John Patrick Aggleton, Matheus Cafalchio, Sean K Martin, Nurul Islam, Shane M OmaraAbstract:Just as hippocampal lesions are principally responsible for "temporal lobe" amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, "diencephalic" amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the Subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology.SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the Subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the Subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the Subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the Subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.
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spatial coding in the Subiculum requires anterior thalamic inputs
Social Science Research Network, 2020Co-Authors: Bethany E Frost, John Patrick Aggleton, Matheus Cafalchio, Sean K Martin, Nurul Islam, Shane M OmaraAbstract:Hippocampal function relies on the anterior thalamic nuclei, yet the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the Subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded Subiculum cells in rats with either permanent (N-methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. The diverse spatial signals normally found in the Subiculum, including place cells, disappeared following permanent thalamic lesions and showed marked disruption during transient lesions. Meanwhile, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance levels, while leaving a non-spatial recognition memory task unaffected. These findings, which help to explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of Subiculum function, and reveal its dependence on anterior thalamic signalling.
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collateral projections innervate the mammillary bodies and retrosplenial cortex a new category of hippocampal cells
eNeuro, 2018Co-Authors: Lisa Kinnavane, Shane M Omara, Seralynne Denise Vann, Andrew J D Nelson, John Patrick AggletonAbstract:To understand the hippocampus, it is necessary to understand the Subiculum. Unlike other hippocampal subfields, the Subiculum projects to almost all distal hippocampal targets, highlighting its critical importance for external networks. The present studies, in male rats and mice, reveal a new category of dorsal Subiculum neurons that innervate both the mammillary bodies (MBs) and the retrosplenial cortex (RSP). These bifurcating neurons comprise almost half of the hippocampal cells that project to RSP. The termination of these numerous collateral projections was visualized within the medial mammillary nucleus and the granular RSP (area 29). These collateral projections included Subiculum efferents that cross to the contralateral MBs. Within the granular RSP, the collateral projections form a particularly dense plexus in deep Layer II and Layer III. This retrosplenial termination site colocalized with markers for VGluT2 and neurotensin. While efferents from the hippocampal CA fields standardly collateralize, Subiculum projections often have only one target site. Consequently, the many collateral projections involving the RSP and the MBs present a relatively unusual pattern for the Subiculum, which presumably relates to how both targets have complementary roles in spatial processing. Furthermore, along with the anterior thalamic nuclei, the MBs and RSP are key members of a memory circuit, which is usually described as both starting and finishing in the hippocampus. The present findings reveal how the hippocampus simultaneously engages different parts of this circuit, so forcing an important revision of this network.
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heterogeneous spatial representation by different subpopulations of neurons in the Subiculum
Neuroscience, 2017Co-Authors: Shane M Omara, Jorge R Brotonsmas, Stefan Schaffelhofer, Christoph Guger, Maria V SanchezvivesAbstract:The Subiculum is a pivotal structure located in the hippocampal formation that receives inputs from grid and place cells and that mediates the output from the hippocampus to cortical and sub-cortical areas. Previous studies have demonstrated the existence of boundary vector cells (BVC) in the Subiculum, as well as exceptional stability during recordings conducted in the dark, suggesting that the Subiculum is involved in the coding of allocentric cues and also in path integration. In order to better understand the role of the Subiculum in spatial processing and the coding of external cues, we recorded subicular units in freely moving rats while performing two experiments: the "size experiment" in which we modified the arena size, and the "barrier experiment" in which we inserted new barriers in a familiar open field thus dividing the enclosure into four comparable sub-chambers. We hypothesized that if physical boundaries were deterministic of the firing of subicular units a strong spatial replication pattern would be found in most spatially modulated units. In contrast, our results demonstrate heterogeneous space coding by different cell types: place cells, barrier-related units and BVC. We also found units characterized by narrow spike waveforms, most likely belonging to axonal recordings, that showed grid-like patterns. Our data indicate that the Subiculum codes space in a flexible manner, and that it is involved in the processing of allocentric information, external cues and path integration, thus broadly supporting spatial navigation.
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roles for the Subiculum in spatial information processing memory motivation and the temporal control of behaviour
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2009Co-Authors: Shane M Omara, Maria V Sanchezvives, Jorge R Brotonsmas, Eugene OhareAbstract:The Subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the Subiculum participates in a wide range of neurocognitive functions and processes. Some of the functions of Subiculum are relatively well-known-these include providing a relatively coarse representation of space and participating in, and supporting certain aspects of, memory (particularly in the dynamic bridging of temporal intervals). The Subiculum also participates in a wide variety of other neurocognitive functions too, however. Much less well-known are roles for the Subiculum, and particularly the ventral Subiculum, in the response to fear, stress and anxiety, and in the generation of motivated behaviour (particularly the behaviour that underlies drug addiction and the response to reward). There is an emerging suggestion that the Subiculum participates in the temporal control of behaviour. It is notable that these latter findings have emerged from a consideration of instrumental behaviour using operant techniques; it may well be the case that the use of the watermaze or similar spatial tasks to assess subicular function (on the presumption that its functions are very similar to the hippocampus proper) has obscured rather than revealed neurocognitive functions of Subiculum. The anatomy of Subiculum suggests it participates in a rather subtle fashion in a very broad range of functions, rather than in a relatively more isolated fashion in a narrower range of functions, as might be the case for "earlier" components of hippocampal circuitry, such as the CA1 and CA3 subfields. Overall, there appears to a strong dorso-ventral segregation of function within Subiculum, with the dorsal Subiculum relatively more concerned with space and memory, and the ventral hippocampus concerned with stress, anxiety and reward. Finally, it may be the case that the whole Subiculum participates in the temporal control of reinforced behaviour, although further experimentation is required to clarify this hypothesis.
Sylvain Williams - One of the best experts on this subject based on the ideXlab platform.
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electrophysiological and morphological characterization of chrna2 cells in the Subiculum and ca1 of the hippocampus an optogenetic investigation
Frontiers in Cellular Neuroscience, 2018Co-Authors: Heather Nichol, Benedicte Amilhon, Frederic Manseau, Saishree Badrinarayanan, Sylvain WilliamsAbstract:The nicotinic acetylcholine receptor alpha2 subunit (Chrna2) is a specific marker for oriens lacunosum-moleculare (OLM) interneurons in the dorsal CA1 region of the hippocampus. It was recently shown using a Chrna2-cre mice line that OLM interneurons can modulate entorhinal cortex and CA3 inputs and may therefore have an important role in gating, encoding, and recall of memory. In this study, we have used a combination of electrophysiology and optogenetics using Chrna2-cre mice to determine the role of Chrna2 interneurons in the Subiculum area, the main output region of the hippocampus. We aimed to assess the similarities between Chrna2 Subiculum and CA1 neurons in terms of the expression of interneuron markers, their membrane properties, and their inhibitory input to pyramidal neurons. We found that Subiculum and CA1 dorsal Chrna2 cells similarly expressed the marker somatostatin and had comparable membrane and firing properties. The somas of Chrna2 cells in both regions were found in the deepest layer with axons projecting superficially. However, Subiculum Chrna2 cells displayed more extensive projections with dendrites which occupied a significantly larger area than in CA1. The post-synaptic responses elicited by Chrna2 cells in pyramidal cells of both regions revealed comparable inhibitory responses elicited by GABAA receptors and, interestingly, GABAB receptor mediated components. This study provides the first in-depth characterization of Chrna2 cells in the Subiculum, and suggests that Subiculum and CA1 Chrna2 cells are generally similar and may play comparable roles in both sub-regions.
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reversal of theta rhythm flow through intact hippocampal circuits
Nature Neuroscience, 2014Co-Authors: Jesse Jackson, Benedicte Amilhon, Romain Goutagny, Jeanbastien Bott, Frederic Manseau, Christian Kortleven, Steven L Bressler, Sylvain WilliamsAbstract:Theta oscillations are thought to propagate unidirectionally along the hippocampal circuitry, from CA3 to CA1 and the Subiculum. In this paper, Jackson and colleagues demonstrate that, in the intact rat hippocampus, theta activity can also flow in reverse from Subiculum to CA3, and find that this phenomenon depends on long-range GABAergic inhibition.
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reversal of theta rhythm flow through intact hippocampal circuits
Nature Neuroscience, 2014Co-Authors: Jesse Jackson, Benedicte Amilhon, Romain Goutagny, Jeanbastien Bott, Frederic Manseau, Christian Kortleven, Steven L Bressler, Sylvain WilliamsAbstract:Activity flow through the hippocampus is thought to arise exclusively from unidirectional excitatory synaptic signaling from CA3 to CA1 to the Subiculum. Theta rhythms are important for hippocampal synchronization during episodic memory processing; thus, it is assumed that theta rhythms follow these excitatory feedforward circuits. To the contrary, we found that theta rhythms generated in the rat Subiculum flowed backward to actively modulate spike timing and local network rhythms in CA1 and CA3. This reversed signaling involved GABAergic mechanisms. However, when hippocampal circuits were physically limited to a lamellar slab, CA3 outputs synchronized CA1 and the Subiculum using excitatory mechanisms, as predicted by classic hippocampal models. Finally, analysis of in vivo recordings revealed that this reversed theta flow was most prominent during REM sleep. These data demonstrate that communication between CA3, CA1 and the Subiculum is not exclusively unidirectional or excitatory and that reversed inhibitory theta signaling also contributes to intrahippocampal synchrony.
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Fast and Slow Gamma Rhythms Are Intrinsically and Independently Generated in the Subiculum
Journal of Neuroscience, 2011Co-Authors: Jesse Jackson, Romain Goutagny, Sylvain WilliamsAbstract:Gamma rhythms are essential for memory encoding and retrieval. Despite extensive study of these rhythms in the entorhinal cortex, dentate gyrus, CA3, and CA1, almost nothing is known regarding their generation and organization in the structure delivering the most prominent hippocampal output: the Subiculum. Here we show using a complete rat hippocampal preparation in vitro that the Subiculum intrinsically and independently generates spontaneous slow (25-50 Hz) and fast (100-150 Hz) gamma rhythms during the rising phase and peak of persistent subicular theta rhythms. These two gamma frequencies are phase modulated by theta rhythms without any form of afferent input from the entorhinal cortex or CA1. Subicular principal cells and interneurons phase lock to both fast and slow gamma, and single cells are independently phase modulated by each form of gamma rhythm, enabling selective participation in neural synchrony at both gamma frequencies at different times. Fast GABAergic inhibition is required for the generation of fast gamma, whereas slow gamma is generated by excitatory and inhibitory mechanisms. In addition, the transverse subicular axis exhibits gamma rhythm topography with faster gamma coupling arising in the distal Subiculum region. The Subiculum therefore possesses a unique intrinsic circuit organization that can autonomously regulate the timing and topography of hippocampal output synchronization. These results suggest the Subiculum is a third spontaneous gamma generator in the hippocampal formation (in addition to CA3 and the entorhinal cortex), and these gamma rhythms likely play an active role in mediating the flow of information between the hippocampus and multiple cortical and subcortical brain regions.
G Sperk - One of the best experts on this subject based on the ideXlab platform.
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changes in the expression of gabaa receptor subunit mrnas in parahippocampal areas after kainic acid induced seizures
Frontiers in Neural Circuits, 2013Co-Authors: Meinrad Drexel, Elke Kirchmair, G SperkAbstract:The parahippocampal areas including the Subiculum, pre- and paraSubiculum and notably the entorhinal cortex are intimately involved in the generation of limbic seizures in temporal lobe epilepsy. We investigated changes in the expression of 10 major GABAA receptor subunit mRNAs in subfields of the ventral hippocampus, ventral Subiculum, entorhinal cortex and perirhinal cortex at different intervals (one, 8, 30 and 90 days) after kainic acid (KA)-induced status epilepticus priming epileptogenesis in the rat. The most pronounced and ubiquitous changes were a transient (24 hrs after KA only) down-regulation of γ2 mRNA and lasting decreases in subunit α5, β3 and δ mRNAs that were prominent in all hippocampal and parahippocampal areas. In the Subiculum similarly as in sectors CA1 and CA3, levels of subunit α1, α2, α4, and γ2 mRNAs decreased transiently (one day after KA-induced status epilepticus). They were followed by increased expression of subunit α1 and α3 mRNAs in the dentate gyryrus and sectors CA1 and CA3, and subunit α1 also in the entorhinal cortex layer II (30 and 90 days after KA). We also observed sustained overexpression of subunits α4 and γ2 in the Subiculum and in the Ammon’s horn. Subunit γ2 mRNA was also increased in sector CA1 at the late intervals after KA. Taken together, our results suggest distinct regulation of mRNA expression for individual GABAA receptor subunits. Especially striking was the wide-spread down-regulation of the often peri- or extra-synaptically located subunits α5 and δ. These subunits are often associated with tonic inhibition. Their decrease could be related to decreased tonic inhibition or may merely reflect compensatory changes. In contrast, expression of subunit α4 that may also also tonic inhibition when associated with the δ subunit was significantly up-regulated in the dentate gyrus and in the proximal Subiculum at late intervals. Thus, concomitant up-regulation of subunit γ2 and α1, α4 mRNAs (and loss in δ subunits) ul
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sequel of spontaneous seizures after kainic acid induced status epilepticus and associated neuropathological changes in the Subiculum and entorhinal cortex
Neuropharmacology, 2012Co-Authors: Meinrad Drexel, Adrian Patrick Preidt, G SperkAbstract:Injection of the seaweed toxin kainic acid (KA) in rats induces a severe status epilepticus initiating complex neuropathological changes in limbic brain areas and subsequently spontaneous recurrent seizures. Although neuropathological changes have been intensively investigated in the hippocampus proper and the dentate gyrus in various seizure models, much less is known about changes in parahippocampal areas. We now established telemetric EEG recordings combined with continuous video monitoring to characterize the development of spontaneous seizures after KA-induced status epilepticus, and investigated associated neurodegenerative changes, astrocyte and microglia proliferation in the Subiculum and other parahippocampal brain areas. The onset of spontaneous seizures was heterogeneous, with an average latency of 15 ± 1.4 days (range 3–36 days) to the initial status epilepticus. The frequency of late spontaneous seizures was higher in rats in which the initial status epilepticus was recurrent after its interruption with diazepam compared to rats in which this treatment was more efficient. Seizure-induced neuropathological changes were assessed in the Subiculum by losses in NeuN-positive neurons and by Fluoro-Jade C staining of degenerating neurons. Neuronal loss was already prominent 24 h after KA injection and only modestly progressed at the later intervals. It was most severe in the proximal Subiculum and in layer III of the medial entorhinal cortex and distinct Fluoro-Jade C labeling was observed there in 75% of rats even after 3 months. Glutamatergic neurons, labeled by in situ hybridization for the vesicular glutamate transporter 1 followed a similar pattern of cell losses, except for the medial entorhinal cortex and the proximal Subiculum that appeared more vulnerable. Glutamate decarboxylase65 (GAD65) mRNA expressing neurons were generally less vulnerable than glutamate neurons. Reactive astrocytes and microglia were present after 24 h, however, became prominent only after 8 days and remained high after 30 days. In the proximal Subiculum, paraSubiculum and entorhinal cortex the number of microglia cells was highest after 30 days. Although numbers of reactive astrocytes and microglia were reduced again after 3 months, they were still present in most rats. The time course of astrocyte and microglia proliferation parallels that of epileptogenesis.
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parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the Subiculum after kainic acid induced seizures
Neuroscience, 2011Co-Authors: Meinrad Drexel, Adrian Patrick Preidt, Elke Kirchmair, G SperkAbstract:The Subiculum is the major output area of the hippocampus. It is closely interconnected with the entorhinal cortex and other parahippocampal areas. In animal models of temporal lobe epilepsy (TLE) and in TLE patients it exerts increased network excitability and may crucially contribute to the propagation of limbic seizures. Using immunohistochemistry and in situ-hybridization we now investigated neuropathological changes affecting parvalbumin and calretinin containing neurons in the Subiculum and other parahippocampal areas after kainic acid-induced status epilepticus. We observed prominent losses in parvalbumin containing interneurons in the Subiculum and entorhinal cortex, and in the principal cell layers of the pre- and paraSubiculum. Degeneration of parvalbumin-positive neurons was associated with significant precipitation of parvalbumin-immunoreactive debris 24 h after kainic acid injection. In the Subiculum the superficial portion of the pyramidal cell layer was more severely affected than its deep part. In the entorhinal cortex, the deep layers were more severely affected than the superficial ones. The decrease in number of parvalbumin-positive neurons in the Subiculum and entorhinal cortex correlated with the number of spontaneous seizures subsequently experienced by the rats. The loss of parvalbumin neurons thus may contribute to the development of spontaneous seizures. On the other hand, surviving parvalbumin neurons revealed markedly increased expression of parvalbumin mRNA notably in the pyramidal cell layer of the Subiculum and in all layers of the entorhinal cortex. This indicates increased activity of these neurons aiming to compensate for the partial loss of this functionally important neuron population. Furthermore, calretinin-positive fibers terminating in the molecular layer of the Subiculum, in sector CA1 of the hippocampus proper and in the entorhinal cortex degenerated together with their presumed perikarya in the thalamic nucleus reuniens. In addition, a significant loss of calretinin containing interneurons was observed in the Subiculum. Notably, the loss in parvalbumin positive neurons in the Subiculum equaled that in human TLE. It may result in marked impairment of feed-forward inhibition of the temporo-ammonic pathway and may significantly contribute to epileptogenesis. Similarly, the loss of calretinin-positive fiber tracts originating from the nucleus reuniens thalami significantly contributes to the rearrangement of neuronal circuitries in the Subiculum and entorhinal cortex during epileptogenesis.
Joachim Behr - One of the best experts on this subject based on the ideXlab platform.
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gating of hippocampal output by β adrenergic receptor activation in the pilocarpine model of epilepsy
Neuroscience, 2015Co-Authors: Sabine Grosser, Janoliver Hollnagel, Kate E Gilling, Julia C Bartsch, Uwe Heinemann, Joachim BehrAbstract:Norepinephrine acting via β-adrenergic receptors (β-ARs) plays an important role in hippocampal plasticity including the Subiculum which is the principal target of CA1 pyramidal cells and which controls information transfer from the hippocampus to other brain regions including the neighboring preSubiculum and the entorhinal cortex (EC). Subicular pyramidal cells are classified as regular- (RS) and burst-spiking (BS) cells. Activation of β-ARs at CA1-Subiculum synapses induces long-term potentiation (LTP) in burst- but not in RS cells (Wojtowicz et al., 2010). To elucidate seizure-associated disturbances in the norepinephrine-dependent modulation of hippocampal output, we investigated the functional consequences of the β-AR-dependent synaptic plasticity at CA1-Subiculum synapses for the transfer of hippocampal output to the parahippocampal region in the pilocarpine model of temporal lobe epilepsy. Using single-cell and multi-channel field recordings in slices, we studied β-AR-mediated changes in the functional connectivity between CA1, the Subiculum and its target-structures. We confirm that application of the β-adrenergic agonist isoproterenol induces LTP in subicular BS- but not RS cells. Due to the distinct spatial distribution of RS- and BS cells in the proximo-to-distal axis of the Subiculum, in field recordings, LTP was significantly stronger in the distal than in the proximal Subiculum. In pilocarpine-treated animals, β-AR-mediated LTP was strongly reduced in the distal Subiculum. The attenuated LTP was associated with a disturbed polysynaptic transmission from the CA1, via the Subiculum to the preSubiculum, but with a preserved transmission to the medial EC. Our findings suggest that synaptic plasticity may influence target-related information flow and that such regulation is disturbed in pilocarpine-treated epileptic rats.
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synaptic plasticity in the Subiculum
Progress in Neurobiology, 2009Co-Authors: Joachim Behr, Christian Wozny, Pawel Fidzinski, Dietmar SchmitzAbstract:The Subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal-cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1-Subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1-Subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output.
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loss of gabaergic neurons in the Subiculum and its functional implications in temporal lobe epilepsy
Brain, 2008Co-Authors: Andreas Knopp, Pawel Fidzinski, Christiane Frahm, Otto W Witte, Joachim BehrAbstract:Clinical and experimental evidence suggest that the Subiculum plays an important role in the maintenance of temporal lobe seizures. Using the pilocarpine-model of temporal lobe epilepsy (TLE), the present study examines the vulnerability of GABAergic subicular interneurons to recurrent seizures and determines its functional implications. In the Subiculum of pilocarpine-treated animals, the density of glutamic acid decarboxylase (GAD) mRNA-positive cells was reduced in all layers. Our data indicate a substantial loss of parvalbumin-immunoreactive neurons in the pyramidal cell and molecular layer whereas calretinin-immunoreactive cells were predominantly reduced in the molecular layer. Though the Subiculum of pilocarpine-treated rats showed an increased intensity of GAD65 immunoreactivity, the density of GAD65 containing synaptic terminals in the pyramidal cell layer was decreased indicating an increase in the GAD65 intensity of surviving synaptic terminals. We observed a decrease in evoked inhibitory post-synaptic currents that mediate dendritic inhibition as well as a decline in the frequency of miniature inhibitory post-synaptic currents (mIPSCs) that are restricted to the perisomatic region. The decrease in mIPSC frequency (-30%) matched with the reduced number of perisomatic GAD-positive terminals (-28%) suggesting a decrease of pre-synaptic GABAergic input onto pyramidal cells in epileptic animals. Though cell loss in the Subiculum has not been considered as a pathogenic factor in human and experimental TLE, our data suggest that the vulnerability of subicular GABAergic interneurons causes an input-specific disturbance of the subicular inhibitory system.
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cellular and network properties of the Subiculum in the pilocarpine model of temporal lobe epilepsy
The Journal of Comparative Neurology, 2005Co-Authors: Andreas Knopp, Uwe Heinemann, Christian Wozny, Anatol Kivi, Joachim BehrAbstract:The Subiculum was recently shown to be crucially involved in the generation of interictal activity in human temporal lobe epilepsy. Using the pilocarpine model of epilepsy, this study examines the anatomical substrates for network hyperexcitability recorded in the Subiculum. Regular- and burst-spiking subicular pyramidal cells were stained with fluorescence dyes and reconstructed to analyze seizure-induced alterations of the dendritic and axonal system. In control animals burst-spiking cells outnumbered regular-spiking cells by about two to one. Regular- and burst-spiking cells were characterized by extensive axonal branching and autapse-like contacts, suggesting a high intrinsic connectivity. In addition, subicular axons projecting to CA1 indicate a CA1-Subiculum-CA1 circuit. In the Subiculum of pilocarpine-treated rats we found an enhanced network excitability characterized by spontaneous rhythmic activity, polysynaptic responses, and all-or-none evoked bursts of action potentials. In pilocarpine-treated rats the Subiculum showed cell loss of about 30%. The ratio of regular- and burst-spiking cells was practically inverse as compared to control preparations. A reduced arborization and spine density in the proximal part of the apical dendrites suggests a partial deafferentiation from CA1. In pilocarpine-treated rats no increased axonal outgrowth of pyramidal cells was observed. Hence, axonal sprouting of subicular pyramidal cells is not mandatory for the development of the pathological events. We suggest that pilocarpine-induced seizures cause an unmasking or strengthening of synaptic contacts within the recurrent subicular network. J. Comp. Neurol. 483:476–488, 2005. © 2005 Wiley-Liss, Inc.
