scholarly journals Glutamate-Bound NMDARs Arising from In Vivo-like Network Activity Extend Spatio-temporal Integration in a L5 Cortical Pyramidal Cell Model

2014 ◽  
Vol 10 (4) ◽  
pp. e1003590 ◽  
Author(s):  
Matteo Farinella ◽  
Daniel T. Ruedt ◽  
Padraig Gleeson ◽  
Frederic Lanore ◽  
R. Angus Silver
Keyword(s):  
Pyramidal Cell ◽  
Cell Model ◽  
Temporal Integration ◽  
Network Activity ◽  
Spatio Temporal ◽  
Cortical Pyramidal Cell

scholarly journals Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

2021 ◽  
Author(s):  
Alison G Costigan ◽  
Katja Umla-Runge ◽  
C John Evans ◽  
Rachel Raybould ◽  
Kim S Graham ◽  
...  
Keyword(s):  
Resting State ◽  
Genetic Risk ◽  
Occipital Cortex ◽  
Network Activity ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Gaba A ◽  
Spatio Temporal ◽  
E4 Allele

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ~20-30 have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN) which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, nor in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Results suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or indeed may precede, alterations in local resting-state PMC neurotransmitters, thus informing the spatio-temporal order and the cause/effect dynamic of neuroimaging differences in APOE E4 carriers.

scholarly journals Computer modeling of hippocampal CA1 pyramidal cells - a tool for in silico experiments

2015 ◽  
Vol 61 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Júlia Metz ◽  
T. Szilágyi ◽  
M. Perian ◽  
K. Orbán-Kis
Keyword(s):  
Pyramidal Cell ◽  
In Silico ◽  
Action Potentials ◽  
Firing Pattern ◽  
Cell Model ◽  
Pyramidal Cells ◽  
Spike Timing ◽  
Network Activity ◽  
Ca1 Pyramidal Cells ◽  
Neuronal Network Activity

Abstract Objective. In silico experiments use mathematical models that capture as much as possible from the properties of the biological system under investigation. Our aim was to test the publicly available CA1 pyramidal cell models using the same simulation tasks, to compare them, and provide a systematic overview of their properties in order to improve the usefulness of these models as a tool for in silico experiments. Methods. Parameters describing the morphology of the cells and the implemented biophysical mechanisms were collected from the Model DB database of Sense Lab Project. This data was analyzed in correlation with the purpose for which each particular model was developed. Multicompartmental simulations were run using the Neuron modeling platform. The properties of the action potentials generated in response to current injection, the firing pattern and the dendritic back-propagation were analyzed. Results. The studied models were optimized to explore different physiological and pathological properties of the CA1 pyramidal cells. We could identify four broad classes of models focusing on: (i) initiation of the action potential, firing pattern and spike timing, (ii) dendritic backpropagation, (iii) dendritic integration of synaptic inputs and (iv) neuronal network activity. Despite the large variation of the active conductances implemented in the models, the properties of the individual action potentials were quite similar, but even the most complex models could not reproduce all studied biological phenomena. Conclusions. At the moment the “perfect” pyramidal cell model is not yet available. Our work, hopefully, will help finding the best model for each scientific question under investigation.

scholarly journals Evidence that PV+ cells enhance temporal population codes but not stimulus-related timing in auditory cortex

2017 ◽  
Author(s):  
Bryan M. Krause ◽  
Caitlin A. Murphy ◽  
Daniel J. Uhlrich ◽  
Matthew I. Banks
Keyword(s):  
Brain Slices ◽  
Pyramidal Cells ◽  
Gamma Oscillations ◽  
Cortical Activity ◽  
Spike Timing ◽  
Network Activity ◽  
Local Network ◽  
Network Bursts ◽  
Spatio Temporal

AbstractSpatio-temporal cortical activity patterns relative to both peripheral input and local network activity carry information about stimulus identity and context. GABAergic interneurons are reported to regulate spiking at millisecond precision in response to sensory stimulation and during gamma oscillations; their role in regulating spike timing during induced network bursts is unclear. We investigated this issue in murine auditory thalamo-cortical (TC) brain slices, in which TC afferents induced network bursts similar to previous reports in vivo. Spike timing relative to TC afferent stimulation during bursts was poor in pyramidal cells and SOM+ interneurons. It was more precise in PV+ interneurons, consistent with their reported contribution to spiking precision in pyramidal cells. Optogenetic suppression of PV+ cells unexpectedly improved afferent-locked spike timing in pyramidal cells. In contrast, our evidence suggests that PV+ cells do regulate the spatio-temporal spike pattern of pyramidal cells during network bursts, whose organization is suited to ensemble coding of stimulus information. Simulations showed that suppressing PV+ cells reduces the capacity of pyramidal cell networks to produce discriminable spike patterns. By dissociating temporal precision with respect to a stimulus versus internal cortical activity, we identified a novel role for GABAergic cells in regulating information processing in cortical networks.

scholarly journals Synaptic Integration in Rat Frontal Cortex Shaped by Network Activity

2005 ◽  
Vol 93 (1) ◽  
pp. 281-293 ◽  
Author(s):  
Jean-François Léger ◽  
Edward A. Stern ◽  
Ad Aertsen ◽  
Detlef Heck
Keyword(s):  
Membrane Potential ◽  
Frontal Cortex ◽  
Temporal Integration ◽  
Synaptic Integration ◽  
Network Activity ◽  
Cortical Function ◽  
Ongoing Activity ◽  
Rat Frontal Cortex

Neocortical neurons in vivo are embedded in networks with intensive ongoing activity. How this network activity affects the neurons’ integrative properties and what function this may imply at the network level remain largely unknown. Most of our knowledge regarding synaptic communication and integration is based on recordings in vitro, where network activity is strongly diminished or even absent. Here, we present results from two complementary series of experiments based on intracellular in vivo recordings in anesthetized rat frontal cortex. Specifically, we measured 1) the relationship between the excursions of a neuron’s membrane potential and the spiking activity in the surrounding network and 2) how the summation of several inputs to a single neuron changes with the different levels of its membrane potential excursions and the associated states of network activity. The combination of these measurements enables us to assess how the level of network activity influences synaptic integration. We present direct evidence that integration of synaptic inputs in frontal cortex is linear, independent of the level of network activity. However, during periods of high network activity, the neurons’ response to synaptic input is markedly reduced in both amplitude and duration. This results in a drastic shortening of its window for temporal integration, requiring more precise coordination of presynaptic spike discharges to reliably drive the neuron to spike under conditions of high network activity. We conclude that ongoing activity, as present in the active brain, emphasizes the need for neuronal cooperation at the network level, and cannot be ignored in the exploration of cortical function.

scholarly journals Internal representation of hippocampal neuronal population span a time-distance continuum

2018 ◽  
Author(s):  
Caroline Haimerl ◽  
David Angulo-Garcia ◽  
Vincent Villette ◽  
Susanne. Reichinnek ◽  
Alessandro Torcini ◽  
...  
Keyword(s):  
Episodic Memory ◽  
Temporal Integration ◽  
Critical Role ◽  
Experimental Studies ◽  
Cell Activity ◽  
Network Activity ◽  
Time And Space ◽  
Distance Information ◽  
Space And Time ◽  
Spatio Temporal

AbstractThe hippocampus plays a critical role in episodic memory: the sequential representation of visited places and experienced events. This function is mirrored by hippocampal activity that self organizes into sequences of neuronal activation that integrate spatio-temporal information. What are the underlying mechanisms of such integration is still unknown. Single cell activity was recently shown to combine time and distance information; however, it remains unknown whether a degree of tuning between space and time can be defined at the network level. Here, combining daily calcium imaging of CA1 sequence dynamics in running head-fixed mice and network modeling, we show that CA1 network activity tends to represent a specific combination of space and time at any given moment, and that the degree of tuning can shift within a continuum from one day to the next. Our computational model shows that this shift in tuning can happen under the control of the external drive power. We propose that extrinsic global inputs shape the nature of spatio-temporal integration in the hippocampus at the population level depending on the task at hand, a hypothesis which may guide future experimental studies.Significance StatementThe hippocampus organizes experience in sequences of events that form episodic memory. How are time and space internally computed in the hippocampus in the absence of sequential external inputs? Here we show that time and space are integrated together within the hippocampal network with different degrees of tuning across days. This was found by recording the activity of hundreds of pyramidal cells for several days. We also propose a mechanism supporting such spatio-temporal integration based on a ring attractor network model: the degree of tuning between space and time can be adjusted by modulating the power of a non-sequential external excitatory drive. In this way, the hippocampus is able to generate a spatio-temporal representation tuned to the task at hand.

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation

2019 ◽  
Vol 133 (20) ◽  
pp. 2045-2059 ◽  
Author(s):  
Da Zhang ◽  
Xiuli Wang ◽  
Siyao Chen ◽  
Selena Chen ◽  
Wen Yu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Endothelial Cell ◽  
Pulmonary Artery ◽  
Cell Model ◽  
Site Directed Mutagenesis ◽  
Critical Event ◽  
Hypertensive Rats ◽  
Pulmonary Artery Endothelial Cell

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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