NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex
25 Nov 2008-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 105, Iss: 47, pp 18572-18577
TL;DR: The two different gamma frequencies matched the different intrinsic frequencies in hippocampal areas CA3 and CA1, suggesting that NMDA receptor activation may control the nature of temporal interactions between mEC and hippocampus, thus influencing the pathway for information transfer between the two regions.
Abstract: Local circuits in the medial entorhinal cortex (mEC) and hippocampus generate gamma frequency population rhythms independently. Temporal interaction between these areas at gamma frequencies is implicated in memory—a phenomenon linked to activity of NMDA-subtype glutamate receptors. While blockade of NMDA receptors does not affect frequency of gamma rhythms in hippocampus, it exposes a second, lower frequency (25–35 Hz) gamma rhythm in mEC. In experiment and model, NMDA receptor-dependent mEC gamma rhythms were mediated by basket interneurons, but NMDA receptor-independent gamma rhythms were mediated by a novel interneuron subtype—the goblet cell. This cell was distinct from basket cells in morphology, intrinsic membrane properties and synaptic inputs. The two different gamma frequencies matched the different intrinsic frequencies in hippocampal areas CA3 and CA1, suggesting that NMDA receptor activation may control the nature of temporal interactions between mEC and hippocampus, thus influencing the pathway for information transfer between the two regions.
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Dissertation•
29 Jun 2015
TL;DR: This thesis develops a two-population spiking attractor network model that is capable of reproducing the activity of a population of grid cells in layer II of the medial entorhinal cortex and shows that theta-nested gamma oscillations can co-exist with grid-like receptive fields generated by the network.
Abstract: The relationship between structure, dynamics, and function of neural networks in nervous systems is still an open question in the neuroscience community. Nevertheless, for certain areas of the mammalian nervous system we do have sufficient data to impose constraints on the organisation of the network structure. One of these areas is the medial entorhinal cortex which contains cells with hexagonally repeating spatial receptive fields, called grid cells. Another intriguing property of entorhinal cortex and other cortical regions is a population oscillatory activity, with frequency in the theta (4-10 Hz) and gamma (30-100 Hz) range. This leads to a question, whether these oscillations are a common circuit mechanism that is functionally relevant and how the oscillatory activity interacts with the computation performed by grid cells. This thesis deals with applying the continuous attractor network theory to modelling of the microcircuit of layer II in the medial entorhinal cortex. Based on recent experimental evidence on connectivity between stellate cells, and fast spiking interneurons, I first develop a two-population spiking attractor network model that is capable of reproducing the activity of a population of grid cells in layer II. The network was implemented with exponential integrate and fire neurons that allowed me to address both the attractor states and the oscillatory activity in this region. Subsequently, I show that the network can produce theta-nested gamma oscillations with properties that are similar to the cross-frequency coupling observed in vivo and in vitro in entorhinal cortex, and that these theta-nested gamma oscillations can co-exist with grid-like receptive fields generated by the network. I also show that the connectivity inspired by anatomical evidence produces a number of directly testable predictions about the firing fields of interneurons in layer II of the medial entorhinal cortex. The excitatory-inhibitory attractor network, together with the theta-nested gamma oscillations, allowed me to explore potential relationships between nested gamma oscillations and grid field computations. I show, by varying the overall level of excitatory and inhibitory synaptic strengths, and levels of noise, in the network, that this relationship is complex, and not easily predictable. Specifically, I show that noise promotes generation of grid firing fields and theta-nested gamma oscillations by the model. I subsequently demonstrate that theta-nested gamma oscillations are dissociable from the grid field computations performed by the network. By changing the relative strengths of interactions between excitatory and inhibitory neurons in the network, the power and frequency of the gamma oscillations changes without disrupting the rate-coded grid field computations. Since grid cells have been suggested to be a part of the spatial cognitive circuit in the brain, these results have potential implications for several cognitive disorders, including autism and schizophrenia, as well as theories that propose a cognitive role for gamma oscillations.
5 citations
Cites background from "NMDA receptor-dependent switching b..."
...Middleton et al. (2008) suggested that the basket cell-dependent oscillations are primarily mediated by NMDA receptors, while goblet cells are not, and thus, block of NMDA receptors disrupts the faster, approximately 40 Hz rhythm....
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...The experimental results have been reproduced by a model that replicated the connectivity between stellate, pyramidal and inhibitory cells in the superficial layers (Middleton et al., 2008)....
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...The frequency of persistent gamma oscillations in entorhinal cortical slices can be switched between two induced frequencies, ∼40 and ∼30 Hz, by the N-methylD-aspartate (NMDA) receptor blocker (Middleton et al., 2008)....
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TL;DR: Using human intracranial recordings, this article found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects.
Abstract: Abstract Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.
4 citations
01 Jan 2018
TL;DR: Findings imply that GluN2C and GLUN2D subunits may be involved in the distinct neural circuitry which regulates neuronal oscillations and thus influence the brain function and contribute to various diseases states.
Abstract: N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects. NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain regions. Recent evidence has shown that GluN2C subunits of NMDAR are expressed in astrocytes in the cortex, and that GluN2D NMDAR subunits are enriched in the parvalbumin-containing GABAergic inhibitory interneurons in the cortex and midbrain structures. Other studies have shown that both astrocytes and parvalbumin-containing interneurons play an essential role in generating and maintaining neuronal oscillations. These findings imply that GluN2C and GluN2D subunits may be involved in the distinct neural circuitry which regulates neuronal oscillations and thus influence the brain function and contribute to various diseases states. The initial aims of this dissertation are to determine if GluN2C and GluN2D subunits have a role in regulating neuronal oscillations. We also measured the auditory evoked responses in wildtype and GluN2Cand GluN2D-KO mice.
4 citations
Cites background from "NMDA receptor-dependent switching b..."
...Studies (Middleton et al., 2008) have shown that NMDAR antagonists can alter the interactions between high gamma and low gamma oscillations in the hippocampus....
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...high gamma band and low gamma band oscillations in hippocampus and entorhinal cortex (Middleton et al., 2008)....
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01 Oct 2012
TL;DR: It is shown that human brain organisation exhibits a topologically central core network within a modular structure consistent with the generation of synchronous oscillation with functional phase dynamics, and two new measures of network centrality, knotty-centrality and set betweenness centrality are developed and applied to empirically derived human structural brain connectivity data.
Abstract: The large-scale integrative mechanisms of the brain, the means by which the activity of functionally segregated neuronal regions are combined, are not well understood. There is growing agreement that a flexible mechanism of integration must be present in order to support the myriad changing cognitive demands under which we are placed. Neuronal communication through phase-coherent oscillation stands as the prominent theory of cognitive integration. The work presented in this thesis explores the role of oscillation and synchronisation in the transfer and integration of information in the brain. It is first shown that complex metastable dynamics suitable for modelling phase-coherent neuronal synchronisation emerge from modularity in networks of delay and pulse-coupled oscillators. Within a restricted parameter regime these networks display a constantly changing set of partially synchronised states where some modules remain highly synchronised while others desynchronise. An examination of network phase dynamics shows increasing coherence with increasing connectivity between modules. The metastable chimera states that emerge from the activity of modular oscillator networks are demonstrated to be synchronous with a constant phase relationship as would be required of a mechanism of large-scale neural integration. A specific example of functional phase-coherent synchronisation within a spiking neural system is then developed. Competitive stimulus selection between converging population encoded stimuli is demonstrated through entrainment of oscillation in receiving neurons. The behaviour of the model is shown to be analogous to well-known competitive processes of stimulus selection such as binocular rivalry, matching key experimentally observed properties for the distribution and correlation of periods of entrainment under differing stimuli strength. Finally two new measures of network centrality, knotty-centrality and set betweenness centrality, are developed and applied to empirically derived human structural brain connectivity data. It is shown that human brain organisation exhibits a topologically central core network within a modular structure consistent with the generation of synchronous oscillation with functional phase dynamics.
4 citations
Cites background from "NMDA receptor-dependent switching b..."
...Different classes of inhibitory interneuron are known to contribute to different frequencies of oscillation (Whittington and Traub, 2003), suggesting potential functional significance of sub-bands within the gamma range (Middleton et al., 2008)....
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TL;DR: In this review, four areas of development predicted to be of importance are explored, including an increase in size and gyrification of the cerebral cortex, increased connectivity between functional areas of the cortex, an expanded role for the subplate in guiding this process, and changes in synapse formation.
4 citations
References
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TL;DR: The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.
Abstract: We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.
2,404 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...This mechanism can underlie gamma rhythms in a broad range of frequencies from around 20 Hz up to 70 Hz in the hippocampus (8) but cannot support higher frequencies such as those labeled as ‘‘high gamma’’ previously (9)....
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TL;DR: It is proposed that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo.
Abstract: Partially synchronous 40-Hz oscillations of cortical neurons have been implicated in cognitive function. Specifically, coherence of these oscillations between different parts of the cortex may provide conjunctive properties to solve the 'binding problem': associating features detected by the cortex into unified perceived objects. Here we report an emergent 40-Hz oscillation in networks of inhibitory neurons connected by synapses using GABAA (gamma-aminobutyric acid) receptors in slices of rat hippocampus and neocortex. These network inhibitory postsynaptic potential oscillations occur in response to the activation of metabotropic glutamate receptors. The oscillations can entrain pyramidal cell discharges. The oscillation frequency is determined both by the net excitation of interneurons and by the kinetics of the inhibitory postsynaptic potentials between them. We propose that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo.
1,625 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...The basic mechanism of generation of population gamma rhythms by local neuronal circuits reveals an absolute dependence on the influence of fast spiking inhibitory interneurons at the level of principal cell somata (5, 6),with the frequency dependent on the magnitude and kinetics of gamma aminobutyric acid (GABAA) receptor-mediated synaptic events (7)....
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TL;DR: It is suggested that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus and that Gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
Abstract: The cellular generation and spatial distribution of gamma frequency (40-100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long axis of the dentate hilus, but average coherence decreased rapidly in the CA3 and CA1 directions. Analysis of short epochs revealed large fluctuations in coherence values between the dentate and CA1 gamma waves. Current source density analysis revealed large sinks and sources in the dentate gyrus with spatial distribution similar to the dipoles evoked by stimulation of the perforant path. The frequency changes of gamma and theta waves positively correlated (40-100 Hz and 5-10 Hz, respectively). Putative interneurons in the dentate gyrus discharged at gamma frequency and were phase-locked to the ascending part of the gamma waves recorded from the hilus. Following bilateral lesion of the entorhinal cortex the power and frequency of hilar gamma activity significantly decreased or disappeared. Instead, a large amplitude but slower gamma pattern (25-50 Hz) emerged in the CA3-CA1 network. We suggest that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus. We also hypothesize that under physiological conditions the hilar gamma oscillation may be entrained by the entorhinal rhythm and that gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
1,529 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...For example, removal of entorhinal cortex in vivo produces a slower gamma rhythm (39), whose origins appear to be in area CA3 (40)....
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TL;DR: This work examines the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes and identifies two gamma generators, one in the dentate gyrus and another in the CA3-CA1 regions.
985 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...For example, removal of entorhinal cortex in vivo produces a slower gamma rhythm (39), whose origins appear to be in area CA3 (40)....
[...]
TL;DR: In this paper, the authors used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding.
Abstract: Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.
899 citations