A novel symbiotic relationship between ascidians and a new tunic-boring polychaete (Annelida: Spionidae: Polydora).

Polydora tunicola Abe, Hoshino Yamada, sp. nov., a new spionid species currently considered an obligate symbiont of styelid ascidians, is described based on materials collected from Polycarpa cf. cryptocarpa kroboja (Oka, 1906) and Cnemidocarpa sp. in Izu-Oshima Island and Polycarpa sp. in Wakayama Prefecture, Japan. Polychaeteascidian symbiotic relationships are known only in two syllid species: Myrianida pinnigera (Montagu, 1808) and Proceraea exoryxae Martin, Nygren Cruz-Rivera, 2017. The latter has been the only polychaete known to bore into the tunic of an ascidian. Polydora tunicola sp. nov. is the second known example of a tunic-boring polychaete, which constructs U-shaped burrows in the tunic of the host ascidians. Worms were often concentrated near the host siphons and assumed to use water currents created by the filter-feeding host for suspension feeding. Although the boring mechanism into ascidian tunica is unknown, the plate assay and zymography results consistently detected cellulase activities, suggesting that cellulose digestion may enable the worms to bore into the cellulose-rich ascidian tunics. Polydora tunicola sp. nov. is morphologically similar to P. aura Sato-Okoshi, 1998, P. cornuta Bosc, 1802, P. fusca Radashevsky Hsieh, 2000, P. glycymerica Radashevsky, 1993, P. latispinosa Blake Kudenov, 1978, P. lingulicola Abe Sato-Okoshi, 2020, P. nanomon Orensky Williams, 2009, P. robi Williams, 2000, and P. vulgaris Mohammad, 1972 in having a single median antenna on the caruncle and chaetiger 5 without dorsal superior capillaries but with ventral capillaries. The new species is unique in having a black-rimmed pygidium, distinguishing it from these species. The phylogenetic analyses of the concatenated 18S, 28S, and 16S sequences recovered P. tunicola sp. nov. as the sister species to P. aura within a well-supported clade also including P. lingulicola and P. cf. glycymerica. The bright yellow body color of P. tunicola sp. nov. in life is similar to that of P. aura, however, these two species are distinguished by the former not having modified posterior notochaetae. The symbiotic nature of the association between P. tunicola sp. nov. and styelid ascidians is discussed.

Effect of cortical extracellular GABA on motor response.

To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory cortical network ([Formula: see text]) and a motor cortical network ([Formula: see text]) are reciprocally connected, and the [Formula: see text] projects to spinal motoneurons (Mns). The [Formula: see text] was presented with a feature stimulus and the reaction time of Mns was measured. The flattening of sensory tuning in [Formula: see text] caused by decreasing the concentration of gamma-aminobutyric acid (GABA) in extracellular space resulted in a decrease in the stimulus-sensitive [Formula: see text] pyramidal cell activity while increasing the stimulus-insensitive [Formula: see text] pyramidal cell activity, thereby prolonging the reaction time of Mns to the applied feature stimulus. We suggest that a reduction in extracellular GABA concentration in sensory cortex may interfere with selective activation in motor cortex, leading to slowing the activation of spinal motoneurons and therefore to slowing motor responses.

Spatiotemporal regulation of GABA concentration in extracellular space by gliotransmission crucial for extrasynaptic receptor-mediated improvement of sensory tuning performance in schizophrenia.

In schizophrenic patients, sensory tuning performance tends to be deteriorated (i.e., flattened sensory tuning), for which impaired intracortical tonic inhibition arising from a reduction in GABA concentration in extracellular space might be responsible. The δ subunit-containing GABAA receptor, located on extrasynaptic sites, is known to be involved in mediating tonic inhibitory currents in cortical pyramidal cells and is considered to be one of the beneficial therapeutic targets for the treatment of schizophrenia. The transporter GAT-1 in glial (astrocytic) membrane controls concentration of GABA molecules by removing them from extracellular space. We speculated that the upregulation of extrasynaptic receptors might compensate for the impaired tonic inhibition and thus improve their sensory tuning performance, in which the astrocytic GABA transporter might play an important role. To test our hypothesis, we simulated a schizophrenic neural network model with a GABAergic gliotransmission (i.e., GABA transport by transporters embedded in astrocytic membranes) mechanism that modulates local ambient (extracellular) GABA levels in a neuronal activity-dependent manner. Upregulating extrasynaptic GABA receptors compensated the impaired tonic inhibition and sharpened the sensory tuning, provided that ambient GABA molecules around stimulus-sensitive pyramidal cells were actively removed during sensory stimulation. We suggest that the upregulation of extrasynaptic GABA receptors can improve the performance of sensory tuning in schizophrenic patients, for which spatiotemporal regulation of ambient GABA concentration by gliotransmission may be crucial.

Reducing variability in motor cortex activity at a resting state by extracellular GABA for reliable perceptual decision-making.

Interaction between sensory and motor cortices is crucial for perceptual decision-making, in which intracortical inhibition might have an important role. We simulated a neural network model consisting of a sensory network (NS) and a motor network (NM) to elucidate the significance of their interaction in perceptual decision-making in association with the level of GABA in extracellular space: extracellular GABA concentration. Extracellular GABA molecules acted on extrasynaptic receptors embedded in membranes of pyramidal cells and suppressed them. A reduction in extracellular GABA concentration either in NS or NM increased the rate of errors in perceptual decision-making, for which an increase in ongoing-spontaneous fluctuations in subthreshold neuronal activity in NM prior to sensory stimulation was responsible. Feedback (NM-to-NS) signaling enhanced selective neuronal responses in NS, which in turn increased stimulus-evoked neuronal activity in NM. We suggest that GABA in extracellular space contributes to reducing variability in motor cortex activity at a resting state and thereby the motor cortex can respond correctly to a subsequent sensory stimulus. Feedback signaling from the motor cortex improves the selective responsiveness of the sensory cortex, which ensures the fidelity of information transmission to the motor cortex, leading to reliable perceptual decision-making.

Extracellular GABA assisting in organizing dynamic cell assemblies to shorten reaction time to sensory stimulation.

Until recently, glia, which exceeds the number of neurons, was considered to only have supportive roles in the central nervous system, providing homeostatic controls and metabolic supports. However, recent studies suggest that glia interacts with neurons and plays active roles in information processing within neuronal circuits. To elucidate how glia contributes to neuronal information processing, we simulated a sensory neuron-glia (neuron-astrocyte) network model. It was investigated in association with ambient (extracellular) GABA level, because the astrocyte has a major role in removing extracellular GABA molecules. In the network model, transporters, embedded in plasma membranes of astrocytes, modulated local ambient GABA levels by actively removing extracellular GABA molecules which persistently acted on receptors in membranes outside synapses and provided pyramidal cells with inhibitory currents. Gap-junction coupling between astrocytes mediated a concordant decrease in local ambient GABA levels, which solicited a prompt population response of pyramidal cells (i.e., activation of an ensemble of pyramidal cells) to a sensory stimulus. As a consequence, the reaction time of a motor network, to which axons of pyramidal cells of the sensory network project, to the sensory stimulus was shortened. We suggest that the astrocytic gap-junction coupling may assist in organizing dynamic cell assemblies by coordinating a reduction in local ambient GABA levels, thereby shortening reaction time to sensory stimulation.

Perceptual judgments via sensory-motor interaction assisted by cortical GABA.

Recurrent input to sensory cortex, via long-range reciprocal projections between motor and sensory cortices, is essential for accurate perceptual judgments. GABA levels in sensory cortices correlate with perceptual performance. We simulated a neuron-astrocyte network model to investigate how top-down, feedback signaling from a motor network (Nmot) to a sensory network (Nsen) affects perceptual judgments in association with ambient (extracellular) GABA levels. In the Nsen, astrocytic transporters modulated ambient GABA levels around pyramidal cells. A simple perceptual task was implemented: detection of a feature stimulus presented to the Nsen. The Nmot showed distinct perceptual behaviors: hit, fault, and miss. A hit is a correct response to the stimulus, a fault is a wrong response to the stimulus, and a miss is no response to the stimulus. In hits, the feedback signaling increased the gain of Nsen pyramidal cells and accelerated the reaction speed of Nmot pyramidal cells to the stimulus. Without feedback signaling, the Nsen but not Nmot responded to the stimulus, resulting in a miss. With too strong feedback signaling, the Nmot resulted in a fault, namely, stimulus-insensitive but not stimulus-sensitive pyramidal cells wrongly responded. Balancing the feedforward and feedback signaling formed a coherent, ongoing-spontaneous neuronal state, by which the highest hit rate was achieved. A transient reduction in local ambient GABA levels, triggered by the stimulus, contributed to accelerating the reaction speed under noisy environmental conditions. Adjusting the basal ambient GABA level ensured high hit rates. We suggest that motor cortex feedback may accelerate reaction speed to sensory stimulation by promoting coherency in ongoing-spontaneous neuronal activity between sensory and motor cortices, thereby achieving prompt perceptual judgments. Spatiotemporal modulation of ambient GABA levels, possibly by astrocytic transporters, assists in making reliable perceptual judgments.

Improved Perceptual Learning by Control of Extracellular GABA Concentration by Astrocytic Gap Junctions.

Learning of sensory cues is believed to rely on synchronous pre- and postsynaptic neuronal firing. Evidence is mounting that such synchronicity is not merely caused by properties of the underlying neuronal network but could also depend on the integrity of gap junctions that connect neurons and astrocytes in networks too. In this perspective, we set out to investigate the effect of astrocytic gap junctions on perceptual learning, introducing a model for coupled neuron-astrocyte networks. In particular, we focus on the fact that astrocytes are rich of GABA transporters (GATs) which can either uptake or release GABA depending on the astrocyte membrane potential, which is a function of local neural activity. We show that GABAergic signaling is a crucial component of intracolumnar neuronal synchronization, thereby promoting learning by neurons in the same cell assembly that are activated by a shared sensory cue. At the same time, we show that this effect can critically depend on astrocytic gap junctions insofar as these latter could synchronize extracellular GABA levels around many neurons and throughout entire cell assemblies. These results are supported by extensive computational arguments and predict that astrocytic gap junctions could improve perceptual learning by controlling extracellular GABA.

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

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 GABAa 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 diffusion across neuronal columns for efficient sensory tuning.

Synaptic (phasic) lateral inhibition between neuronal columns mediated by GABAergic interneurons is, in general, essential for primary sensory cortices to respond selectively to elemental features. We propose here a neural network model with a nonsynaptic (tonic) lateral inhibitory mechanism. While firing, intrasynaptic GABA molecules spill over into extracellular space and accumulate in neuronal columns. Through accumulation in and diffusion across these columns, a level of ambient (extracellular) GABA changes in a neuronal activity-dependent manner. Ambient GABA molecules act on extrasynaptic receptors and provide neurons with tonic inhibitory currents. We examined whether and how the diffusion of GABA molecules across neuronal columns affects tuning performance of the network to a feature stimulus: selective responsiveness. The GABA diffusion led to reducing ambient GABA in the stimulus-relevant column while augmenting ambient GABA in stimulus-irrelevant columns, thereby improving the tuning performance. The GABA diffusion was effective especially when provided with a broader sensory input. Interestingly, this diffusion-based, nonsynaptic (tonic) lateral inhibitory scheme worked well together with the conventional, synaptic (phasic) lateral inhibitory scheme, enhancing the sensory tuning. We suggest that the nonsynaptic lateral inhibition, mediated through GABA diffusion across neuronal columns, may be beneficial for the cortex to tune to sensory features.

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.

Facilitation of neuronal responses by intrinsic default mode network activity.

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.

Tonically balancing intracortical excitation and inhibition by GABAergic gliotransmission.

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.

Balanced crossmodal excitation and inhibition essential for maximizing multisensory gain.

We examined whether and how the balancing of crossmodal excitation and inhibition affects intersensory facilitation. A neural network model, comprising lower-order unimodal networks (X, Y) and a higher-order multimodal network (M), was simulated. Crossmodal excitation was made by direct activation of principal cells of the X network by the Y network. Crossmodal inhibition was made in an indirect manner: the Y network activated glial cells of the X network. This let glial plasma membrane transporters export GABA molecules into the extracellular space and increased the level of ambient GABA. The ambient GABA molecules were accepted by extrasynaptic GABAa receptors and tonically inhibited principal cells of the X network. Namely, crossmodal inhibition was made through GABAergic gliotransmission. Intersensory facilitation was assessed in terms of multisensory gain: the difference between the numbers of spikes evoked by multisensory (XY) stimulation and unisensory (X-alone) stimulation. The maximal multisensory gain (XY-X) could be achieved at an intermediate noise level by balancing crossmodal excitation and inhibition. This result supports an experimentally derived conclusion: intersensory facilitation under noisy environmental conditions is not necessarily in accord with the principle of inverse effectiveness; rather, multisensory gain is maximal at intermediate signal-to-noise ratio (SNR) levels. The maximal multisensory gain was available at the weakest signal if noise was not present, indicating that the principle of inverse effectiveness is a special case of the intersensory facilitation model proposed here. We suggest that the balancing of crossmodal excitation and inhibition may be crucial for intersensory facilitation. The GABAergic glio-transmission-mediated crossmodal inhibitory mechanism effectively works for intersensory facilitation and on determining the maximal multisensory gain in the entire SNR range between the two extremes: low and high SNRs.

Deficient GABAergic gliotransmission may cause broader sensory tuning in schizophrenia.

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.

Ambient GABA responsible for age-related changes in multistable perception.

Multistable perception is a psychophysical phenomenon in which one unique interpretation alternates spontaneously every few seconds between two or more interpretations of the same sensory input. Well-known examples include the Necker cube and face-vase illusions in vision. Interestingly, young adults generally see more perceptual switches than do elderly people. To understand the underlying neuronal mechanism of age-related multistable perception, we simulated a cortical neural network model that consists of multiple cell assemblies. In the network, a specific population of noncore cells and a common population of core cells form a cell assembly that represents a single object (or event). Every dynamic cell assembly, activated by a given sensory input, involves the common (overlapping) population of core cells. Ambient GABA-mediated intracortical tonic inhibition via extrasynaptic GABAa receptors destabilized the currently appearing dynamic cell assembly and terminated its burst firing. This allowed another dynamic cell assembly to emerge one after the other. Namely, multistable perception took place. Transporters, which were embedded in axon terminal membranes of interneurons, regulated levels of ambient GABA. For elderly people, we assumed a decline in transporter. This decelerated GABA augmentation and resulted in prolonging the durations of burst firing and thus in slowing perceptual switches. We suggest that poor control of ambient GABA levels due to age-related decline in GABA transporter may be responsible for the slowing of perceptual switches in elderly people.

Dynamic modulation of an orientation preference map by GABA responsible for age-related cognitive performance.

Accumulating evidence suggests that cognitive declines in old (healthy) animals could arise from depression of intracortical inhibition, for which a decreased ability to produce GABA during senescence might be responsible. By simulating a neural network model of a primary visual cortical (V1) area, we investigated whether and how a lack of GABA affects cognitive performance of the network: detection of the orientation of a visual bar-stimulus. The network was composed of pyramidal (P) cells and GABAergic interneurons such as small (S) and large (L) basket cells. Intrasynaptic GABA-release from presynaptic S or L cells contributed to reducing ongoing-spontaneous (background) neuronal activity in a different manner. Namely, the former exerted feedback (S-to-P) inhibition and reduced the frequency (firing rate) of action potentials evoked in P cells. The latter reduced the number of saliently firing P cells through lateral (L-to-P) inhibition. Non-vesicular GABA-release, presumably from glia and/or neurons, into the extracellular space reduced the both, activating extrasynaptic GABAa receptors and providing P cells with tonic inhibitory currents. By this combinatorial, spatiotemporal inhibitory mechanism, the background activity as noise was significantly reduced, compared to the stimulus-evoked activity as signal, thereby improving signal-to-noise (S/N) ratio. Interestingly, GABA-spillover from the intrasynaptic cleft into the extracellular space was effective for improving orientation selectivity (orientation bias), especially when distractors interfered with detecting the bar-stimulus. These simulation results may provide some insight into how the depression of intracortical inhibition due to a reduction in GABA content in the brain leads to age-related cognitive decline.

Regulation of ambient GABA levels by neuron-glia signaling for reliable perception of multisensory events.

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 GABA(a) 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.

Diffusive feedback influences on hierarchical information processing.

In visual information processing, feedforward projection from primary to secondary visual cortex (V1-to-V2) is essential for integrating combinations of oriented bars in order to extract angular information embedded within contours that represent the shape of objects. For feedback (V2-to-V1) projection, two distinct types of pathways have been observed: clustered projection and diffused projection. The former innervates V1 domains with a preferred orientation similar to that of V2 cells of origin. In contrast, the latter innervates without such orientation specificity. V2 cells send their axons to V1 domains with both similar and dissimilar orientation preferences. It is speculated that the clustered feedback projection has a role in contour integration. The role of the diffused feedback projection, however, remains to be seen. We simulated a minimal, functional V1-V2 neural network model. The diffused feedback projection contributed to achieving ongoing-spontaneous subthreshold membrane oscillations in V1 cells, thereby reducing the reaction time of V1 cells to a pair of bars that represents specific angular information. Interestingly, the feedback influence took place even before V2 responses, which might stem largely from ongoing-spontaneous signaling from V2. We suggest that the diffusive feedback influence from V2 could act early in V1 responses and accelerate their reaction speed to sensory stimulation in order to rapidly extract angular information.

Subthreshold membrane depolarization as memory trace for perceptual learning.

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 GABA(a) 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.

Neuronal responses below firing threshold for subthreshold cross-modal enhancement.

Multisensory integration (such as somatosensation-vision, gustation-olfaction) could occur even between subthreshold stimuli that in isolation do not reach perceptual awareness. For example, when a somatosensory (subthreshold) stimulus is delivered within a close spatiotemporal congruency, a visual (subthreshold) stimulus evokes a visual percept. Cross-modal enhancement of visual perception is maximal when the somatosensory stimulation precedes the visual one by tens of milliseconds. This rapid modulatory response would not be consistent with a top-down mechanism acting through higher-order multimodal cortical areas, but rather a direct interaction between lower-order unimodal areas. To elucidate the neuronal mechanisms of subthreshold cross-modal enhancement, we simulated a neural network model. In the model, lower unimodal (X, Y) and higher multimodal (M) networks are reciprocally connected by bottom-up and top-down axonal projections. The lower networks are laterally connected with each other. A pair of stimuli was presented to the lower networks, whose respective intensities were too weak to induce salient neuronal activity (population response) when presented alone. Neurons of the Y network were slightly depolarized below firing threshold when a cross-modal stimulus was presented alone to the X network. This allowed the Y network to make a rapid (within tens of milliseconds) population response when presented with a subsequent congruent stimulus. The reaction speed of the Y network was accelerated, provided that the top-down projections were strengthened. We suggest that a subthreshold (nonpopulation) response to a cross-modal stimulus, acting through interaction between lower (primary unisensory) areas, may be essential for a rapid suprathreshold (population) response to a congruent stimulus that follows. Top-down influences on cross-modal enhancement may be faster than expected, accelerating reaction speed to input, in which ongoing-spontaneous subthreshold excitation of lower-order unimodal cells by higher-order multimodal cells may play an active role.