Regulation of Local Ambient GABA Levels via Transporter-Mediated GABA Import and Export for Subliminal Learning

Perception of supraliminal stimuli might in general be reflected in bursts of action potentials (spikes), and their memory traces could be formed through spike-timing-dependent plasticity (STDP). Memory traces for subliminal stimuli might be formed in a different manner, because subliminal stimulation evokes a fraction (but not a burst) of spikes. Simulations of a cortical neural network model showed that a subliminal stimulus that was too brief (10 msec) to perceive transiently (more than about 500 msec) depolarized stimulus-relevant principal cells and hyperpolarized stimulus-irrelevant principal cells in a subthreshold manner. This led to a small increase or decrease in ongoing-spontaneous spiking activity frequency (less than 1 Hz). Synaptic modification based on STDP during this period effectively enhanced relevant synaptic weights, by which subliminal learning was improved. GABA transporters on GABAergic interneurons modulated local levels of ambient GABA. Ambient GABA molecules acted on extrasynaptic receptors, provided principal cells with tonic inhibitory currents, and contributed to achieving the subthreshold neuronal state. We suggest that ongoing-spontaneous synaptic alteration through STDP following subliminal stimulation may be a possible neuronal mechanism for leaving its memory trace in cortical circuitry. Regulation of local ambient GABA levels by transporter-mediated GABA import and export may be crucial for subliminal learning.

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STDP Forms Associations between Memory Traces in Networks of Spiking Neurons

Cerebral Cortex ◽

10.1093/cercor/bhz140 ◽

2019 ◽

Vol 30 (3) ◽

pp. 952-968

Author(s):

Christoph Pokorny ◽

Matias J Ison ◽

Arjun Rao ◽

Robert Legenstein ◽

Christos Papadimitriou ◽

...

Keyword(s):

Brain Function ◽

Spatial Information ◽

Spike Timing ◽

Spiking Neurons ◽

Recurrent Networks ◽

Neural Codes ◽

Memory Traces ◽

Conflicting Evidence ◽

Excitability Of Neurons ◽

The Brain

Abstract Memory traces and associations between them are fundamental for cognitive brain function. Neuron recordings suggest that distributed assemblies of neurons in the brain serve as memory traces for spatial information, real-world items, and concepts. However, there is conflicting evidence regarding neural codes for associated memory traces. Some studies suggest the emergence of overlaps between assemblies during an association, while others suggest that the assemblies themselves remain largely unchanged and new assemblies emerge as neural codes for associated memory items. Here we study the emergence of neural codes for associated memory items in a generic computational model of recurrent networks of spiking neurons with a data-constrained rule for spike-timing-dependent plasticity. The model depends critically on 2 parameters, which control the excitability of neurons and the scale of initial synaptic weights. By modifying these 2 parameters, the model can reproduce both experimental data from the human brain on the fast formation of associations through emergent overlaps between assemblies, and rodent data where new neurons are recruited to encode the associated memories. Hence, our findings suggest that the brain can use both of these 2 neural codes for associations, and dynamically switch between them during consolidation.

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Tonically Balancing Intracortical Excitation and Inhibition by GABAergic Gliotransmission

Neural Computation ◽

10.1162/neco_a_00612 ◽

2014 ◽

Vol 26 (8) ◽

pp. 1690-1716 ◽

Cited By ~ 2

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.

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Regulation of Ambient GABA Levels by Neuron-Glia Signaling for Reliable Perception of Multisensory Events

Neural Computation ◽

10.1162/neco_a_00356 ◽

2012 ◽

Vol 24 (11) ◽

pp. 2964-2993 ◽

Cited By ~ 16

Author(s):

Osamu Hoshino

Keyword(s):

Glial Cells ◽

Extracellular Space ◽

Sensory Modality ◽

Gabaergic Interneuron ◽

Gain Function ◽

Principal Cells ◽

Ambient Gaba ◽

The Cross ◽

Multisensory Information ◽

Stimulation Of

Activities of sensory-specific cortices are known to be suppressed when presented with a different sensory modality stimulus. This is referred to as cross-modal inhibition, for which the conventional synaptic mechanism is unlikely to work. Interestingly, the cross-modal inhibition could be eliminated when presented with multisensory stimuli arising from the same event. To elucidate the underlying neuronal mechanism of cross-modal inhibition and understand its significance for multisensory information processing, we simulated a neural network model. Principal cell to and GABAergic interneuron to glial cell projections were assumed between and within lower-order unimodal networks (X and Y), respectively. Cross-modality stimulation of Y network activated its principal cells, which then depolarized glial cells of X network. This let transporters on the glial cells export GABA molecules into the extracellular space and increased a level of ambient (extrasynaptic) GABA. The ambient GABA molecules were accepted by extrasynaptic GABAa receptors and tonically inhibited principal cells of the X network. Cross-modal inhibition took place in a nonsynaptic manner. Identical modality stimulation of X network activated its principal cells, which then activated interneurons and hyperpolarized glial cells of the X network. This let their transporters import (remove) GABA molecules from the extracellular space and reduced tonic inhibitory current in principal cells, thereby improving their gain function. Top-down signals from a higher-order multimodal network (M) contributed to elimination of the cross-modal inhibition when presented with multisensory stimuli that arose from the same event. Tuning into the multisensory event deteriorated if the cross-modal inhibitory mechanism did not work. We suggest that neuron-glia signaling may regulate local ambient GABA levels in order to coordinate cross-modal inhibition and improve neuronal gain function, thereby achieving reliable perception of multisensory events.

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The Transmembrane Sodium Gradient Influences Ambient GABA Concentration by Altering the Equilibrium of GABA Transporters

Journal of Neurophysiology ◽

10.1152/jn.00545.2006 ◽

2006 ◽

Vol 96 (5) ◽

pp. 2425-2436 ◽

Cited By ~ 37

Author(s):

Yuanming Wu ◽

Wengang Wang ◽

George B. Richerson

Keyword(s):

Hippocampal Slices ◽

Gaba Release ◽

Synaptic Cleft ◽

Tonic Inhibition ◽

Multiple Sources ◽

Sodium Removal ◽

Gaba Transporters ◽

Sodium Gradient ◽

Ambient Gaba ◽

Tonic Current

Tonic inhibition is widely believed to be caused solely by “spillover” of GABA that escapes the synaptic cleft and activates extrasynaptic GABAA receptors. However, an exclusively vesicular source is not consistent with the observation that tonic inhibition can still occur after blocking vesicular release. Here, we made patch-clamp recordings from neurons in rat hippocampal cultures and measured the tonic current that was blocked by bicuculline or gabazine. During perforated patch recordings, the tonic GABA current was decreased by the GAT1 antagonist SKF-89976a. Zero calcium solution did not change the amount of tonic current, despite a large reduction in vesicular GABA release. Perturbations that would be expected to alter the transmembrane sodium gradient influenced the tonic current. For example, in zero calcium Ringer, TTX (which can decrease cytosolic [Na+]) reduced tonic current, whereas veratridine (which can increase cytosolic [Na+]) increased tonic current. Likewise, removal of extracellular sodium led to a large increase in tonic current. The increases in tonic current induced by veratridine and sodium removal were completely blocked by SKF89976a. When these experiments were repeated in hippocampal slices, similar results were obtained except that a GAT1- and GAT3-independent nonvesicular source(s) of GABA was found to contribute to the tonic current. We conclude that multiple sources can contribute to ambient GABA, including spillover and GAT1 reversal. The source of GABA release may be conceptually less important in determining the amount of tonic inhibition than the factors that control the equilibrium of GABA transporters.

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Facilitation of Neuronal Responses by Intrinsic Default Mode Network Activity

Neural Computation ◽

10.1162/neco_a_00660 ◽

2014 ◽

Vol 26 (11) ◽

pp. 2441-2464 ◽

Cited By ~ 1

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.

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Tonic GABAA conductance favors temporal over rate coding in the rat hippocampus

10.1101/738369 ◽

2019 ◽

Author(s):

Yulia Dembitskaya ◽

Yu-Wei Wu ◽

Alexey Semyanov

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Spike Timing ◽

Network Activity ◽

Neuronal Network Activity ◽

Term Potentiation ◽

Rate Coding ◽

Ambient Gaba ◽

Theta Burst

AbstractSynaptic plasticity is triggered by different patterns of neuronal network activity. Network activity leads to an increase in ambient GABA concentration and tonic activation of GABAA receptors. How tonic GABAA conductance affects synaptic plasticity during temporal and rate-based coding is poorly understood. Here, we show that tonic GABAA conductance differently affects long-term potentiation (LTP) induced by different stimulation patterns. The LTP based on a temporal spike - EPSP order (spike-timing-dependent [st] LTP) was not affected by exogenous GABA application. Backpropagating action potential, which enables Ca2+ entry through N-methyl-D-aspartate receptors (NMDARs) during stLTP induction, was only slightly reduced by the tonic conductance. In contrast, GABA application impeded LTP dependent on spiking rate (theta-burst-induced [tb] LTP) by reducing the EPSP bust response and, hence, NMDAR-mediated Ca2+ entry during tbLTP induction. Our results may explain the changes in different forms of memory under physiological and pathological conditions that affect tonic GABAA conductance.

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Subthreshold Membrane Depolarization as Memory Trace for Perceptual Learning

Neural Computation ◽

10.1162/neco_a_00211 ◽

2011 ◽

Vol 23 (12) ◽

pp. 3205-3231 ◽

Cited By ~ 15

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.

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Regulation of spontaneous rhythmic activity and organization of pacemakers as memory traces by spike-timing-dependent synaptic plasticity in a hippocampal model

Physical Review E ◽

10.1103/physreve.69.011910 ◽

2004 ◽

Vol 69 (1) ◽

Cited By ~ 10

Author(s):

Motoharu Yoshida ◽

Hatsuo Hayashi

Keyword(s):

Synaptic Plasticity ◽

Rhythmic Activity ◽

Spike Timing ◽

Memory Traces ◽

Spontaneous Rhythmic Activity

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STDP forms associations between memory traces in networks of spiking neurons

10.1101/188938 ◽

2017 ◽

Cited By ~ 1

Author(s):

Christoph Pokorny ◽

Matias J. Ison ◽

Arjun Rao ◽

Robert Legenstein ◽

Christos Papadimitriou ◽

...

Keyword(s):

Brain Function ◽

Spatial Information ◽

Spike Timing ◽

Spiking Neurons ◽

Neural Codes ◽

Memory Traces ◽

Conflicting Evidence ◽

Two Parameters ◽

Excitability Of Neurons ◽

The Brain

AbstractMemory traces and associations between them are fundamental for cognitive brain function. Neuron recordings suggest that distributed assemblies of neurons in the brain serve as memory traces for spatial information, real-world items, and concepts. How-ever, there is conflicting evidence regarding neural codes for associated memory traces. Some studies suggest the emergence of overlaps between assemblies during an association, while others suggest that the assemblies themselves remain largely unchanged and new assemblies emerge as neural codes for associated memory items. Here we study the emergence of neural codes for associated memory items in a generic computational model of recurrent networks of spiking neurons with a data-constrained rule for spike-timing-dependent plasticity (STDP). The model depends critically on two parameters, which control the excitability of neurons and the scale of initial synaptic weights. By modifying these two parameters, the model can reproduce both experimental data from the human brain on the fast formation of associations through emergent overlaps between assemblies, and rodent data where new neurons are recruited to encode the associated memories. Hence our findings suggest that the brain can use both of these two neural codes for associations, and dynamically switch between them during consolidation.

Download Full-text