Categorical judgments do not modify sensory representations in working memory

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to reverse their categorical judgments about a stimulus feature, if incorrect, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials. We found no traces of the initial categorical judgment. Rather, subjects seemed to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectations in the subsequent sensory recall and inference process.     

A computer model of generation of the motor cortex neuron processes seen in the course of execution of instrumental movement

A computer model of neuronal processes in the motor cortex column is presented. The model is consisted of two pyramidal cell layers with two groups of inhibitory interneurons, selectively controlling pyramidal cell soma and dendrite, in each. Active Na, Ca and K conductances are included in the model of a single neuron. Horizontal excitatory connections between pyramidal cells in the upper layer are largely of NMDA-receptor type, that in the lower layer--of non-NMDA-type. All inhibitory synapses are of GABA(A)-type. The model reproduces the main phenomenon observed in the motor cortex during the execution of conditioned movements. Consequent to an early excitation the upper layer pyramidal cells generate a late NMDA-dependent reflexive response to afferent conditional stimulation, which as in a real case is diminished by GABA(A)-type synaptic inhibition and afferent stimulus strength increase. The characteristic inverse relation between the late response manifestation and the stimulus strength observed in the real cortex can be reproduced in the model only if NMDA-glutamate receptors were preferentially localized in the terminals of pyramidal cell backward collaterals, not in the terminals of the afferent fibers on pyramidal neurons. The intended component of motor cortex neuronal activity is generated in NMDA-independent manner by the pyramidal cells of lower layer. The slow time coarse of intended component as compared with short duration of AMPA epsp's is due to a consecutive relay-race--like activation of pyramidal neurons with different dendrit-to-soma ratio.     

Glutamate Uptake Triggers Transporter-Mediated GABA Release from Astrocytes

Background

Glutamate (Glu) and γ-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes.

Methodology/Principal Findings

Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca²⁺ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process.

Conclusions/Significance

Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia.     

Multisensory interplay reveals crossmodal influences on 'sensory-specific' brain regions, neural responses, and judgments

Although much traditional sensory research has studied each sensory modality in isolation, there has been a recent explosion of interest in causal interplay between different senses. Various techniques have now identified numerous multisensory convergence zones in the brain. Some convergence may arise surprisingly close to low-level sensory-specific cortex, and some direct connections may exist even between primary sensory cortices. A variety of multisensory phenomena have now been reported in which sensory-specific brain responses and perceptual judgments concerning one sense can be affected by relations with other senses. We survey recent progress in this multisensory field, foregrounding human studies against the background of invasive animal work and highlighting possible underlying mechanisms. These include rapid feedforward integration, possible thalamic influences, and/or feedback from multisensory regions to sensory-specific brain areas. Multisensory interplay is more prevalent than classic modular approaches assumed, and new methods are now available to determine the underlying circuits.     

Modulation of Matrix Metalloproteinases Activity in the Ventral Horn of the Spinal Cord Re-stores Neuroglial Synaptic Homeostasis and Neurotrophic Support following Peripheral Nerve Injury

Modulation of extracellular matrix (ECM) remodeling after peripheral nerve injury (PNI) could represent a valid therapeutic strategy to prevent maladaptive synaptic plasticity in central nervous system (CNS). Inhibition of matrix metalloproteinases (MMPs) and maintaining a neurotrophic support could represent two approaches to prevent or reduce the maladaptive plastic changes in the ventral horn of spinal cord following PNI. The purpose of our study was to analyze changes in the ventral horn produced by gliopathy determined by the suffering of motor neurons following spared nerve injury (SNI) of the sciatic nerve and how the intrathecal (i.t.) administration of GM6001 (a MMPs inhibitor) or the NGF mimetic peptide BB14 modulate these events. Immunohistochemical analysis of spinal cord sections revealed that motor neuron disease following SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) response in the ventral horn of the spinal cord, indicative of reactive gliosis. These changes were paralleled by decreased glial aminoacid transporters (glutamate GLT1 and glycine GlyT1), increased levels of the neuronal glutamate transporter EAAC1, and a net increase of the Glutamate/GABA ratio, as measured by HPLC analysis. These molecular changes correlated to a significant reduction of mature NGF levels in the ventral horn. Continuous i.t. infusion of both GM6001 and BB14 reduced reactive astrogliosis, recovered the expression of neuronal and glial transporters, lowering the Glutamate/GABA ratio. Inhibition of MMPs by GM6001 significantly increased mature NGF levels, but it was absolutely ineffective in modifying the reactivity of microglia cells. Therefore, MMPs inhibition, although supplies neurotrophic support to ECM components and restores neuro-glial transporters expression, differently modulates astrocytic and microglial response after PNI.     

Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission

GABA synthesis is necessary to maintain synaptic vesicle filling, and key proteins in its biosynthetic pathways may play a role in regulating inhibitory synaptic stability and strength. GABAergic neurons require a source of precursor glutamate, possibly from glutamine, although it is controversial whether glutamine contributes to the synaptic pool of GABA. Here we report that inhibition of System A glutamine transporters with alpha-(methyl-amino) isobutyric acid rapidly reduced the amplitude of inhibitory post-synaptic currents and miniature inhibitory post-synaptic currents (mIPSCs) recorded in rat hippocampal area cornu ammonis 1 (CA1) pyramidal neurons, indicating that synaptic vesicle content of GABA was reduced. After inhibiting astrocytic glutamine synthesis by either blocking glutamate transporters or the glutamine synthetic enzyme, the effect of alpha-(methyl-amino) isobutyric acid on mIPSC amplitudes was abolished. Exogenous glutamine did not affect mIPSC amplitudes, suggesting that the neuronal transporters are normally saturated. Our findings demonstrate that a constitutive supply of glutamine is provided by astrocytes to inhibitory neurons to maintain vesicle filling. Therefore, glutamine transporters, like those for glutamate, are potential regulators of inhibitory synaptic strength. However, in contrast to glutamate, extracellular glutamine levels are normally high. Therefore, we propose a supportive role for glutamine, even under resting conditions, to maintain GABA vesicle filling.     

Perceptual learning and sensomotor flexibility: cortical plasticity under attentional control?

Recent research reveals long-lasting cortical plasticity of early sensory cortices even in adults. Sensory signals could be modified under top-down control if necessary quite early in order to optimize their signal-to-noise ratio, leading to 'low level' or 'early' perceptual learning (PL). For easy tasks, such elaborate top-down influences are usually not required, and learning is restricted to late selection of the appropriate signals on higher cortical levels, which seems easier and faster to achieve. But to reach the absolute limits of sensory performance, PL seems to optimize the entire chain of sensory processing. Hence, improvement for these extreme perceptual abilities is quite specific for a number of stimulus parameters, such as the position in the visual field and sometimes even the trained eye, reflecting the specificity of receptive fields in early sensory cortices. Early PL may be just one example--even if a very extensive one--of the mechanisms of neuronal plasticity and sensomotor flexibility that are constantly updating our sensomotor representations as a result of experience. As an illustration, this review contains some new experimental results on PL and sensory flexibility in the context of adaptation to multifocal intraocular lenses.     

Distributed representation of perceptual categories in the auditory cortex

Categorical perception is a process by which a continuous stimulus space is partitioned to represent discrete sensory events. Early experience has been shown to shape categorical perception and enlarge cortical representations of experienced stimuli in the sensory cortex. The present study examines the hypothesis that enlargement in cortical stimulus representations is a mechanism of categorical perception. Perceptual discrimination and identification behaviors were analyzed in model auditory cortices that incorporated sound exposure-induced plasticity effects. The model auditory cortex with over-representations of specific stimuli exhibited categorical perception behaviors for those specific stimuli. These results indicate that enlarged stimulus representations in the sensory cortex may be a mechanism for categorical perceptual learning.     

Experience‐dependent plasticity of dendritic spines of layer 2/3 pyramidal neurons in the mouse cortex

Previous studies have shown that sensory and motor experiences play an important role in the remodeling of dendritic spines of layer 5 (L5) pyramidal neurons in the cortex. In this study, we examined the effects of sensory deprivation and motor learning on dendritic spine remodeling of layer 2/3 (L2/3) pyramidal neurons in the barrel and motor cortices. Similar to L5 pyramidal neurons, spines on apical dendrites of L2/3 pyramidal neurons are plastic during development and largely stable in adulthood. Sensory deprivation via whisker trimming reduces the elimination rate of existing spines without significant effect on the rate of spine formation in the developing barrel cortex. Furthermore, we show that motor training increases the formation and elimination of dendritic spines in the primary motor cortex. Unlike L5 pyramidal neurons, however, there is no significant difference in the rate of spine formation between sibling dendritic branches of L2/3 pyramidal neurons. Our studies indicate that sensory and motor learning experiences have important impact on dendritic spine remodeling in L2/3 pyramidal neurons. They also suggest that the rules governing experience‐dependent spine remodeling are largely similar, but not identical, between L2/3 and L5 pyramidal neurons. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 277–286, 2016     

Attention controls multisensory perception via two distinct mechanisms at different levels of the cortical hierarchy

To form a percept of the multisensory world, the brain needs to integrate signals from common sources weighted by their reliabilities and segregate those from independent sources. Previously, we have shown that anterior parietal cortices combine sensory signals into representations that take into account the signals’ causal structure (i.e., common versus independent sources) and their sensory reliabilities as predicted by Bayesian causal inference. The current study asks to what extent and how attentional mechanisms can actively control how sensory signals are combined for perceptual inference. In a pre- and postcueing paradigm, we presented observers with audiovisual signals at variable spatial disparities. Observers were precued to attend to auditory or visual modalities prior to stimulus presentation and postcued to report their perceived auditory or visual location. Combining psychophysics, functional magnetic resonance imaging (fMRI), and Bayesian modelling, we demonstrate that the brain moulds multisensory inference via two distinct mechanisms. Prestimulus attention to vision enhances the reliability and influence of visual inputs on spatial representations in visual and posterior parietal cortices. Poststimulus report determines how parietal cortices flexibly combine sensory estimates into spatial representations consistent with Bayesian causal inference. Our results show that distinct neural mechanisms control how signals are combined for perceptual inference at different levels of the cortical hierarchy.

A combination of psychophysics, computational modelling and fMRI reveals novel insights into how the brain controls the binding of information across the senses, such as the voice and lip movements of a speaker.     

Adaptation to visual feedback delay influences visuomotor learning

Computational theory of motor control suggests that the brain continuously monitors motor commands, to predict their sensory consequences before actual sensory feedback becomes available. Such prediction error is a driving force of motor learning, and therefore appropriate associations between motor commands and delayed sensory feedback signals are crucial. Indeed, artificially introduced delays in visual feedback have been reported to degrade motor learning. However, considering our perceptual ability to causally bind our own actions with sensory feedback, demonstrated by the decrease in the perceived time delay following repeated exposure to an artificial delay, we hypothesized that such perceptual binding might alleviate deficits of motor learning associated with delayed visual feedback. Here, we evaluated this hypothesis by investigating the ability of human participants to adapt their reaching movements in response to a novel visuomotor environment with 3 visual feedback conditions--no-delay, sudden-delay, and adapted-delay. To introduce novelty into the trials, the cursor position, which originally indicated the hand position in baseline trials, was rotated around the starting position. In contrast to the no-delay condition, a 200-ms delay was artificially introduced between the cursor and hand positions during the presence of visual rotation (sudden-delay condition), or before the application of visual rotation (adapted-delay condition). We compared the learning rate (representing how the movement error modifies the movement direction in the subsequent trial) between the 3 conditions. In comparison with the no-delay condition, the learning rate was significantly degraded for the sudden-delay condition. However, this degradation was significantly alleviated by prior exposure to the delay (adapted-delay condition). Our data indicate the importance of appropriate temporal associations between motor commands and sensory feedback in visuomotor learning. Moreover, they suggest that the brain is able to account for such temporal associations in a flexible manner.     

Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation

Background

Glutamate and ??-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.

Results

Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na⁺ concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg²⁺] in vitro model of epilepsy. Under in vivo conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.

Conclusions

The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons.     

Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size

The functional balance of glutamatergic and GABAergic signaling in neuronal cortical circuits is under homeostatic control. That is, prolonged alterations of global network activity leads to opposite changes in quantal amplitude at glutamatergic and GABAergic synapses. Such scaling of excitatory and inhibitory transmission within cortical circuits serves to restore and maintain a constant spontaneous firing rate of pyramidal neurons. Our recent work shows that this includes alterations in the levels of expression of vesicular glutamate (VGLUT1 and VGLUT2) and GABA (VIAAT) transporters. Other vesicle markers, such as synaptophysin or synapsin, are not regulated in this way. Endogenous regulation at the level of mRNA and synaptic protein controls the number of transporters per vesicle and hence, the level of vesicle filling with transmitter. Bidirectional and opposite activity-dependent regulation of VGLUT1 and VIAAT expression would serve to adjust the balance of glutamate and GABA release and therefore the level of postsynaptic receptor saturation. In some excitatory neurons and synapses, co-expression of VGLUT1 and VGLUT2 occurs. Bidirectional and opposite changes in the levels of two excitatory vesicular transporters would enable individual neocortical neurons to scale up or scale down the level of vesicular glutamate storage, and thus, the amount available for release at individual synapses. Regulated vesicular transmitter storage and release via selective changes in the level of expression of vesicular glutamate and GABA transporters indicates that homeostatic plasticity of synaptic strength at cortical synapses includes presynaptic elements.     

TRANSMITTER METABOLIZING ENZYMES AND FREE AMINO ACID LEVELS IN SENSORY AND MOTOR NERVES AND GANGLIA OF THE SHORE CRAB (CARCINUS MAENAS)

—The distribution of ChAT (choline acetyltransferase), GAD (glutamate decarboxylase) and acetylcholinesterase in some sensory and motor nerves of the shore crab, Carcinus maenas, has been investigated using micro-assay techniques. ChAT was concentrated in the afferent nerve fibres of the thoracic-coxal muscle receptor as well as in the coxo-basal chordotonal receptor nerve and other leg sensory fibres. GAD was found in leg motor nerves including the promotor and remotor muscle nerves, being undetectable in the sensory nerves. Acetylcholinesterase was found in similar levels in both sensory and motor nerves assayed. Amino acid analysis using a micro-dansylation technique showed that sensory nerves had low GABA levels, whereas the leg nerve including motor fibres had substantially higher GABA concentrations. GAD and GABA were also found in low amounts in the leg promoter mucle, which is consistent with GABA being a neuromuscular transmitter.     

Touch Interacts with Vision during Binocular Rivalry with a Tight Orientation Tuning

Multisensory integration is a common feature of the mammalian brain that allows it to deal more efficiently with the ambiguity of sensory input by combining complementary signals from several sensory sources. Growing evidence suggests that multisensory interactions can occur as early as primary sensory cortices. Here we present incompatible visual signals (orthogonal gratings) to each eye to create visual competition between monocular inputs in primary visual cortex where binocular combination would normally take place. The incompatibility prevents binocular fusion and triggers an ambiguous perceptual response in which the two images are perceived one at a time in an irregular alternation. One key function of multisensory integration is to minimize perceptual ambiguity by exploiting cross-sensory congruence. We show that a haptic signal matching one of the visual alternatives helps disambiguate visual perception during binocular rivalry by both prolonging the dominance period of the congruent visual stimulus and by shortening its suppression period. Importantly, this interaction is strictly tuned for orientation, with a mismatch as small as 7.5° between visual and haptic orientations sufficient to annul the interaction. These results indicate important conclusions: first, that vision and touch interact at early levels of visual processing where interocular conflicts are first detected and orientation tunings are narrow, and second, that haptic input can influence visual signals outside of visual awareness, bringing a stimulus made invisible by binocular rivalry suppression back to awareness sooner than would occur without congruent haptic input.     

Brain states: top-down influences in sensory processing

All cortical and thalamic levels of sensory processing are subject to powerful top-down influences, the shaping of lower-level processes by more complex information. New findings on the diversity of top-down interactions show that cortical areas function as adaptive processors, being subject to attention, expectation, and perceptual task. Brain states are determined by the interactions between multiple cortical areas and the modulation of intrinsic circuits by feedback connections. In perceptual learning, both the encoding and recall of learned information involves a selection of the appropriate inputs that convey information about the stimulus being discriminated. Disruption of this interaction may lead to behavioral disorders, including schizophrenia.     

Perceptual learning: specificity versus generalization

Perceptual learning improves performance on many tasks, from orientation discrimination to the identification of faces. Although conventional wisdom considered sensory cortices as hard-wired, the specificity of improvement achieved through perceptual learning indicates an involvement of early sensory cortices. These cortices might be more plastic than previously assumed, and both sum-potential and single cell recordings indeed demonstrate plasticity of neuronal responses of these sensory cortices. However, for learning to be optimally useful, it must generalize to other tasks. Further research on perceptual learning should therefore, in my opinion, investigate first, the conditions for generalization of training-induced improvement, second, its use for teaching and rehabilitation, and third, its dependence on pharmacological agents.     

11C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.     

Reshaping sensory representations by task-specific brain states: Toward cortical circuit mechanisms

Perception is internally constructed by integrating brain states with external sensory inputs, a process depending on the topdown modulation of sensory representations. A wealth of earlier studies described task-dependent modulations of sensory cortex corroborating perceptual and behavioral phenomena. But only with recent technological advancements, the underlying circuit-level mechanisms began to be unveiled. We review recent progress along this line of research. It begins to be appreciated that topdown signals can encode various types of task-related information, ranging from task engagement, and category knowledge to decision execution; these signals are transferred via feedback pathways originating from distinct association cortices and interact with sensory cortical circuits. These plausible mechanisms support a broad range of computations from predictive coding to inference making, ultimately form dynamic percepts and endow behavioral flexibility.