Reduction of Trial-to-Trial Perceptual Variability by Intracortical Tonic Inhibition

2016 ◽  
Vol 28 (1) ◽  
pp. 187-215 ◽  
Author(s):  
Osamu Hoshino ◽  
Meihong Zheng ◽  
Kazuo Watanabe
Keyword(s):  
Neuronal Activity ◽  
Network Model ◽  
Dependent Manner ◽  
Gaba Concentration ◽  
Cell Assemblies ◽  
Principal Cells ◽  
Ambient Gaba ◽  
Spontaneous Neuronal Activity ◽  
Perceptual Variability ◽  
Feature Stimulus

Variability is a prominent characteristic of cognitive brain function. For instance, different trials of presentation of the same stimulus yield higher variability in its perception: subjects sometimes fail in perceiving the same stimulus. Perceptual variability could be attributable to ongoing-spontaneous fluctuation in neuronal activity prior to sensory stimulation. Simulating a cortical neural network model, we investigated the underlying neuronal mechanism of perceptual variability in relation to variability in ongoing-spontaneous neuronal activity. In the network model, populations of principal cells (cell assemblies) encode information about sensory features. Each cell assembly is sensitive to one particular feature stimulus. Transporters on GABAergic interneurons regulate ambient GABA concentration in a neuronal activity-dependent manner. Ambient GABA molecules activate extrasynaptic GABA[Formula: see text] receptors on principal cells and interneurons, and provide them with tonic inhibitory currents. We controlled the variability of ongoing-spontaneous neuronal activity by manipulating the basal level of ambient GABA and assessed the perceptual performance of the network: detection of a feature stimulus. In an erroneous response, stimulus-irrelevant but not stimulus-relevant principal cells were activated, generating trains of action potentials. Perceptual variability, reflected in error rate in detecting the same stimulus that was presented repeatedly to the network, was increased as the variability in ongoing-spontaneous membrane potential among cell assemblies increased. Frequent, transient membrane depolarization below firing threshold was the major cause of the increased neuronal variability, for which a decrease in basal ambient GABA concentration was responsible. We suggest that ambient GABA in the brain may have a role in reducing the variability in ongoing-spontaneous neuronal activity, leading to a decrease in perceptual variability and therefore to reliable sensory perception.

GABA Transporter Preserving Ongoing Spontaneous Neuronal Activity at Firing Subthreshold

2009 ◽  
Vol 21 (6) ◽  
pp. 1683-1713 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Neuronal Activity ◽  
Extracellular Space ◽  
Transport Mechanism ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Gaba Transporter ◽  
Cell Assemblies ◽  
Time Period ◽  
Ambient Gaba ◽  
Spontaneous Neuronal Activity

There has been compelling evidence that the GABA transporter is crucial not only for removing gamma-aminobutyric acid (GABA) from but also releasing it into extracellular space, thereby clamping ambient GABA (GABA in extracellular space) at a certain level. The ambient GABA is known to activate extrasynaptic GABA receptors and provide tonic inhibitory current into neurons. We investigated how the transporter regulates the level of ambient GABA, mediates tonic neuronal inhibition, and influences ongoing spontaneous neuronal activity. A cortical neural network model is proposed in which GABA transporters on lateral (L) and feedback (F) inhibitory (GABAergic) interneurons are functionally made. Principal (P) cell assemblies participate in expressing information about elemental sensory features. At membrane potentials below the reversal potential, there is net influx of GABA, whereas at membrane potentials above the reversal potential, there is net efflux of GABA. Through this transport mechanism, ambient GABA concentration is kept within a submicromolar range during an ongoing spontaneous neuronal activity time period. Here we show that the GABA transporter on L cells regulates the overall level of ambient GABA across cell assemblies, and that on F cells it does so within individual cell assemblies. This combinatorial regulation of ambient GABA allows P cells to oscillate near firing threshold during the ongoing time period, thereby reducing their reaction time to externally applied stimuli. We suggest that the GABA transporter, with its forward and reverse transport mechanism, could regulate the ambient GABA. This transporter-mediated ambient GABA regulation may contribute to establishing an ongoing subthreshold neuronal state by which the network can respond rapidly to subsequent sensory input.

Deficient GABAergic Gliotransmission May Cause Broader Sensory Tuning in Schizophrenia

2013 ◽  
Vol 25 (12) ◽  
pp. 3235-3262 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Glial Cell ◽  
Glial Cells ◽  
Extracellular Space ◽  
Regulatory Mechanism ◽  
Intracortical Inhibition ◽  
Gaba Concentration ◽  
Principal Cells ◽  
Dynamic Cell ◽  
Ambient Gaba ◽  
Feature Stimulus

We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial-cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the regulation of local ambient GABA levels, thereby improving the sensory tuning performance of the cortex.

Tonically Balancing Intracortical Excitation and Inhibition by GABAergic Gliotransmission

2014 ◽  
Vol 26 (8) ◽  
pp. 1690-1716 ◽  
Author(s):  
Meihong Zheng ◽  
Takami Matsuo ◽  
Ai Miyamoto ◽  
Osamu Hoshino
Keyword(s):  
Extracellular Space ◽  
Plasma Membranes ◽  
Sensory Information ◽  
Inhibitory Mechanism ◽  
Neuronal Responses ◽  
Gaba Concentration ◽  
Cell Assemblies ◽  
Gaba Transporters ◽  
Ambient Gaba ◽  
P Cells

For sensory cortices to respond reliably to feature stimuli, the balancing of neuronal excitation and inhibition is crucial. A typical example might be the balancing of phasic excitation within cell assemblies and phasic inhibition between cell assemblies. The former controls the gain of and the latter the tuning of neuronal responses. A change in ambient GABA concentration might affect the dynamic behavior of neurons in a tonic manner. For instance, an increase in ambient GABA concentration enhances the activation of extrasynaptic receptors, augments an inhibitory current, and thus inhibits neurons. When a decrease in ambient GABA concentration occurs, the tonic inhibitory current is reduced, and thus the neurons are relatively excited. We simulated a neural network model in order to examine whether and how such a tonic excitatory-inhibitory mechanism could work for sensory information processing. The network consists of cell assemblies. Each cell assembly, comprising principal cells (P), GABAergic interneurons (Ia, Ib), and glial cells (glia), responds to one particular feature stimulus. GABA transporters, embedded in glial plasma membranes, regulate ambient GABA levels. Hypothetical neuron-glia signaling via inhibitory (Ia-to-glia) and excitatory (P-to-glia) synaptic contacts was assumed. The former let transporters import (remove) GABA from the extracellular space and excited stimulus-relevant P cells. The latter let them export GABA into the extracellular space and inhibited stimulus-irrelevant P cells. The main finding was that the glial membrane transporter gave a combinatorial excitatory-inhibitory effect on P cells in a tonic manner, thereby improving the gain and tuning of neuronal responses. Interestingly, it worked cooperatively with the conventional, phasic excitatory-inhibitory mechanism. We suggest that the GABAergic gliotransmission mechanism may provide balanced intracortical excitation and inhibition so that the best perceptual performance of the cortex can be achieved.

Facilitation of Neuronal Responses by Intrinsic Default Mode Network Activity

2014 ◽  
Vol 26 (11) ◽  
pp. 2441-2464 ◽  
Author(s):  
Hiroakira Matsui ◽  
Meihong Zheng ◽  
Osamu Hoshino
Keyword(s):  
Glial Cells ◽  
Default Mode Network ◽  
Network Activity ◽  
Gaba Concentration ◽  
Default Mode ◽  
Model Network ◽  
Principal Cells ◽  
Ambient Gaba ◽  
Glial Membrane ◽  
Reaction Speed

Default mode network (DMN) shows intrinsic, high-level activity at rest. We tested a hypothesis proposed for its role in sensory information processing: Intrinsic DMN activity facilitates neural responses to sensory input. A neural network model, consisting of a sensory network (Nsen) and a DMN, was simulated. The Nsen contained cell assemblies. Each cell assembly comprised principal cells, GABAergic interneurons (Ia, Ib), and glial cells. We let the Nsen carry out a perceptual task: detection of sensory stimuli. During DMN activation, glial cells were hyperpolarized by Ia-to-glia circuitry, by which glial membrane transporters imported GABA molecules from the extracellular space and decreased ambient GABA concentration. Acting on extrasynaptic GABA receptors, the decrease in ambient GABA concentration reduced inhibitory current in a tonic manner. This depolarized principal cells below their firing threshold during the ongoing spontaneous time period and accelerated their reaction speed to a sensory stimulus. During the stimulus presentation period, the Nsen inhibited the DMN and caused DMN deactivation. The DMN deactivation made Nsen Ia cells cease firing, thereby stopping the glial membrane hyperpolarization, quitting the GABA import, returning to the basal ambient GABA level, and thus enhancing global inhibition. Notably, the stimulus-relevant P cell firing could be maintained when GABAergic gliotransmission via Ia-glia signaling worked, decreasing ambient GABA concentration around the stimulus-relevant P cells. This enabled the Nsen to reliably detect the stimulus. We suggest that intrinsic default model network activity may accelerate the reaction speed of the sensory network by modulating its ongoing-spontaneous activity in a subthreshold manner. Ambient GABA contributes to achieve an optimal ongoing spontaneous subthreshold neuronal state, in which GABAergic gliotransmission triggered by the intrinsic default model network activity may play an important role.

Subthreshold Membrane Depolarization as Memory Trace for Perceptual Learning

2011 ◽  
Vol 23 (12) ◽  
pp. 3205-3231 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Perceptual Learning ◽  
Memory Trace ◽  
Neuronal Response ◽  
Membrane Depolarization ◽  
Spike Timing ◽  
Chemical Agent ◽  
Gabaergic Interneurons ◽  
Dependent Manner ◽  
Gaba Concentration ◽  
Ambient Gaba

Experience-dependent synaptic plasticity characterizes the adaptable brain and is believed to be the cellular substrate for perceptual learning. A chemical agent such as gamma-aminobutyric acid (GABA) is known to affect synaptic alteration, perhaps gating perceptual learning. We examined whether and how ambient (extrasynaptic) GABA affects experience-dependent synaptic alteration. A cortical neural network model was simulated. Transporters on GABAergic interneurons regulate ambient GABA levels around their axonal target neurons by removing GABA from (forward transport) or releasing it into (reverse transport) the extracellular space. The ambient GABA provides neurons with tonic inhibitory currents by activating extrasynaptic GABAa receptors. During repeated exposures to the same stimulus, we modified the synaptic connection strength between principal cells in a spike-timing-dependent manner. This modulated the activity of GABAergic interneurons, and reduced or augmented ambient GABA concentration. Reduction in ambient GABA concentration led to slight depolarization (less than several millivolts) in ongoing-spontaneous membrane potential. This was a subthreshold neuronal behavior because ongoing-spontaneous spiking activity remained almost unchanged. The ongoing-spontaneous subthreshold depolarization improved a suprathreshold neuronal response. If the stimulus was long absent for perceptual learning, augmentation of ambient GABA concentration took place and the ongoing-spontaneous subthreshold depolarization was depressed. We suggest that a perceptual memory trace could be left in neuronal circuitry as an ongoing-spontaneous subthreshold membrane depolarization, which would allow that memory to be accessed easily afterward, whereas a trace of a memory that has not recently been retrieved fades away when the ongoing-spontaneous subthreshold membrane depolarization built by previous perceptual learning is depressed. This would lead that memory to be accessed with some difficulty. In the brain, ambient GABA, whose level could be regulated by transporter may have an important role in leaving memory trace for perceptual learning.

An Ongoing Subthreshold Neuronal State Established Through Dynamic Coassembling of Cortical Cells

2008 ◽  
Vol 20 (12) ◽  
pp. 3055-3086 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Neuronal Activity ◽  
Network Model ◽  
Sensory Stimulation ◽  
Local Network ◽  
Activity Period ◽  
Cell Assembly ◽  
Core Nucleus ◽  
Cell Assemblies ◽  
Transient Dynamic ◽  
The Core

Ensemble activation of neurons, triggered or spontaneous, sometimes involves a common (overlapping) neuronal population known as core cells. It is speculated that the core cells functioning as a core nucleus have a role in dictating noncore cells' behavior and thus overall local network dynamics. However, the truth and its significance in neuronal information processing still remain to be seen. To address this issue, a neural network model of an early sensory cortical area was simulated. In the network model, noncore cells that have selective responsiveness to sensory features constituted noncore cell assemblies. Core cells, having unselective responsiveness, constituted a single core cell assembly. Sensory stimulation activated neuronal ensembles that were indistinguishable from those activated spontaneously. The core cells were active in every ensemble activation and recruited a changing complement of noncore cells, which varied from spontaneous event to spontaneous event or from triggered event to triggered event. Ensemble activation of neurons was established through what we call dynamic coassembling, in which the core cell assembly and one of the noncore cell assemblies were dynamically linked together. Transient dynamic coassembling frequently and randomly took place during the ongoing (spontaneous) neuronal activity period, and persistent dynamic coassembling did during the stimulus-triggered neuronal activity period. The frequent ongoing activation of core cells mediated through transient dynamic coassembling depolarized noncore cells just below firing threshold, whereby the noncore cells could respond rapidly to sensory stimulation. The persistent dynamic coassembling enhanced the responsiveness of noncore cells. We suggest that the core cells, functioning as a core nucleus, dictate how the noncore cells oscillate at a subthreshold level during the ongoing period and how to respond when stimulated. The transient and persistent dynamic coassembling may be an essential neuronal mechanism for the cortex to prepare and respond effectively to sensory input.

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

2021 ◽  
pp. 1-16
Author(s):  
Masaki Nakano ◽  
Yachiyo Mitsuishi ◽  
Lei Liu ◽  
Naoki Watanabe ◽  
Emi Hibino ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Extracellular Release ◽  
Activity Dependent ◽  
Aβ Production

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

Longitudinal Changes in Cerebellar and Thalamic Spontaneous Neuronal Activity After Wide-Awake Surgery of Brain Tumors: a Resting-State fMRI Study

2015 ◽  
Vol 15 (4) ◽  
pp. 451-465 ◽  
Author(s):  
Anthony Boyer ◽  
Jérémy Deverdun ◽  
Hugues Duffau ◽  
Emmanuelle Le Bars ◽  
François Molino ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Neuronal Activity ◽  
Resting State ◽  
Resting State Fmri ◽  
Awake Surgery ◽  
Longitudinal Changes ◽  
Fmri Study ◽  
Spontaneous Neuronal Activity ◽  
Wide Awake

scholarly journals GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons

2017 ◽  
Vol 118 (6) ◽  
pp. 3092-3106 ◽  
Author(s):  
Michael Moldavan ◽  
Olga Cravetchi ◽  
Charles N. Allen
Keyword(s):  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Dependent Manner ◽  
Circadian Period ◽  
Gaba Concentration ◽  
Gaba Transporter ◽  
Concentration Dependent Manner ◽  
Gaba Transport ◽  
Gaba Transporters ◽  
Tonic Current

GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN. NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

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