Stimulus-specific Activity Research Articles

Stimulus specific cortical activity associated with ignoring distraction during working memory encoding and maintenance

Distraction disrupts Working Memory (WM) performance, but how the brain filters distraction is not known. One possibility is that neural activity associated with distractions is suppressed relative to a baseline/passive task (biased competition). Alternatively, distraction may be denied access to WM, with no suppression. Furthermore, behavioural work indicates separate mechanisms for ignoring distractions which occur (1) while we put information into WM (Encoding Distraction, ED) and (2) while we maintain already encoded information during the WM delay period (Delay Distraction, DD). Here we used fMRI in humans to measure category-sensitive cortical activity and probe the extent to which ED/DD mechanisms involve enhancement/suppression during a WM task. We observed significant enhancement of task-relevant activity, relative to a passive view task, which did not differ according to whether or when distractors appeared. For both ED and DD we found no evidence of suppression, but instead a robust increase in stimulus specific activity in response to additional stimuli presented during the passive view task, which was not seen for the WM task, when those additional stimuli were to be ignored. The results indicate that ED/DD resistance does not necessarily involve suppression of distractor-related activity. Rather, a rise in distractor-associated activity is prevented when distractors are presented, supporting models of input gating, and providing a potential mechanism by which input-gating might be achieved.

Prior expectations evoke stimulus-specific activity in the deep layers of the primary visual cortex.

The way we perceive the world is strongly influenced by our expectations. In line with this, much recent research has revealed that prior expectations strongly modulate sensory processing. However, the neural circuitry through which the brain integrates external sensory inputs with internal expectation signals remains unknown. In order to understand the computational architecture of the cortex, we need to investigate the way these signals flow through the cortical layers. This is crucial because the different cortical layers have distinct intra- and interregional connectivity patterns, and therefore determining which layers are involved in a cortical computation can inform us on the sources and targets of these signals. Here, we used ultra-high field (7T) functional magnetic resonance imaging (fMRI) to reveal that prior expectations evoke stimulus-specific activity selectively in the deep layers of the primary visual cortex (V1). These findings are in line with predictive processing theories proposing that neurons in the deep cortical layers represent perceptual hypotheses and thereby shed light on the computational architecture of cortex.

A crabs' high‐order brain center resolved as a mushroom body‐like structure

The hypothesis of a common origin for high-order memory centers in bilateral animals presents the question of how different brain structures, such as the vertebrate hippocampus and the arthropod mushroom bodies, are both structurally and functionally comparable. Obtaining evidence to support the hypothesis that crustaceans possess structures equivalent to the mushroom bodies that play a role in associative memories has proved challenging. Structural evidence supports that the hemiellipsoid bodies of hermit crabs, crayfish and lobsters, spiny lobsters, and shrimps are homologous to insect mushroom bodies. Although a preliminary description and functional evidence supporting such homology in true crabs (Brachyura) has recently been shown, other authors consider the identification of a possible mushroom body homolog in Brachyura as problematic. Here we present morphological and immunohistochemical data in Neohelice granulata supporting that crabs possess well-developed hemiellipsoid bodies that are resolved as mushroom bodies-like structures. Neohelice exhibits a peduncle-like tract, from which processes project into proximal and distal domains with different neuronal specializations. The proximal domains exhibit spines and en passant-like processes and are proposed here as regions mainly receiving inputs. The distal domains exhibit a "trauben"-like compartmentalized structure with bulky terminal specializations and are proposed here as output regions. In addition, we found microglomeruli-like complexes, adult neurogenesis, aminergic innervation, and elevated expression of proteins necessary for memory processes. Finally, in vivo calcium imaging suggests that, as in insect mushroom bodies, the output regions exhibit stimulus-specific activity. Our results support the shared organization of memory centers across crustaceans and insects.

Electrophysiological mechanisms of human memory consolidation

Consolidation stabilizes memory traces after initial encoding. Rodent studies suggest that memory consolidation depends on replay of stimulus-specific activity patterns during fast hippocampal “ripple” oscillations. Here, we measured replay in intracranial electroencephalography recordings in human epilepsy patients, and related replay to ripples. Stimulus-specific activity was identified using representational similarity analysis and then tracked during waking rest and sleep after encoding. Stimulus-specific gamma (30–90 Hz) activity during early (100–500 ms) and late (500–1200 ms) encoding is spontaneously reactivated during waking state and sleep, independent of later memory. Ripples during nREM sleep, but not during waking state, trigger replay of activity from the late time window specifically for remembered items. Ripple-triggered replay of activity from the early time window during nREM sleep is enhanced for forgotten items. These results provide the first electrophysiological evidence for replay related to memory consolidation in humans, and point to a prominent role of nREM ripple-triggered replay in consolidation processes.

Variation in Genome-Wide NF-κB RELA Binding Sites upon Microbial Stimuli and Identification of a Virus Response Profile.

NF-κB transcription factors are master regulators of the innate immune response. Activated downstream of pathogen recognition receptors, they regulate the expression of genes to help fight infections as well as recruit the adaptive immune system. NF-κB responds to a wide variety of signals, but the processes by which stimulus specificity is attained remain unclear. In this article, we characterized the response of one NF-κB member, RELA, to four stimuli mimicking infection in human nasopharyngeal epithelial cells. Comparing genome-wide RELA binding, we observed stimulus-specific sites, although most sites overlapped across stimuli. Specifically, the response to poly I:C (mimicking viral dsRNA and signaling through TLR3) induced a distinct RELA profile, binding in the vicinity of antiviral genes and correlating with corresponding gene expression. This group of binding sites was also enriched in IFN regulatory factor motifs and showed overlapping with IFN regulatory factor binding sites. A novel NF-κB target, OASL, was further validated and showed TLR3-specific activation. This work showed that some RELA DNA binding sites varied in activation response following different stimulations and that interaction with more specialized factors could help achieve this stimulus-specific activity. Our data provide a genomic view of regulated host response to different pathogen stimuli.

Psychosis subgroups differ in intrinsic neural activity but not task-specific processing

Individuals with psychosis often show high levels of intrinsic, or nonspecific, neural activity, but attenuated stimulus-specific activity. Clementz et al. (2016) proposed that one subgroup of psychosis cases has accentuated intrinsic activity (Biotype-2's) and a different subgroup (Biotype-1's) has diminished intrinsic activity, with both groups exhibiting varying degrees of cognitive deficits. This model was studied by assessing neural activity in psychosis probands (N=105) during baseline and a 5second period in preparation for a pro-/anti-saccade task. Steady-state stimuli allowed real-time assessment of modulation of visuocortical investment to different target locations.Psychosis probands as a whole showed poor antisaccade performance. As expected, Biotype-1 showed diminished intrinsic neural activity and the worst behavior, and Biotype-2 showed accentuated intrinsic activity and less deviant behavior. Both of these groups also exhibited less dynamic oscillatory phase synchrony. Biotype-3 showed no neurophysiological differences from healthy individuals, despite a history of psychosis. Interestingly, all psychosis subgroups showed normal (i.e., not different from healthy) preparatory modulation of visuocortical investment as a function of cognitive demands, despite varying levels of task performance. Similar analyses conducted subgrouping cases by psychotic symptomatology revealed fewer and less consistent differences, including no intrinsic activity differences between any clinical subgroup and healthy individuals. This study illustrates that (i) differences in intrinsic neural activity may be a fundamental characteristic of psychosis and need to be evaluated separately from stimulus-specific responses, and (ii) grouping patients based on multidimensional classification using neurobiological data may have advantages for resolving heterogeneity and clarifying illness mechanisms relative to traditional psychiatric diagnoses.

Laminar differences in response to simple and spectro-temporally complex sounds in the primary auditory cortex of ketamine-anesthetized gerbils.

In mammals, acoustic communication plays an important role during social behaviors. Despite their ethological relevance, the mechanisms by which the auditory cortex represents different communication call properties remain elusive. Recent studies have pointed out that communication-sound encoding could be based on discharge patterns of neuronal populations. Following this idea, we investigated whether the activity of local neuronal networks, such as those occurring within individual cortical columns, is sufficient for distinguishing between sounds that differed in their spectro-temporal properties. To accomplish this aim, we analyzed simple pure-tone and complex communication call elicited multi-unit activity (MUA) as well as local field potentials (LFP), and current source density (CSD) waveforms at the single-layer and columnar level from the primary auditory cortex of anesthetized Mongolian gerbils. Multi-dimensional scaling analysis was used to evaluate the degree of “call-specificity” in the evoked activity. The results showed that whole laminar profiles segregated 1.8-2.6 times better across calls than single-layer activity. Also, laminar LFP and CSD profiles segregated better than MUA profiles. Significant differences between CSD profiles evoked by different sounds were more pronounced at mid and late latencies in the granular and infragranular layers and these differences were based on the absence and/or presence of current sinks and on sink timing. The stimulus-specific activity patterns observed within cortical columns suggests that the joint activity of local cortical populations (as local as single columns) could indeed be important for encoding sounds that differ in their acoustic attributes.

Massive Effect on LncRNAs in Human Monocytes During Fungal and Bacterial Infections and in Response to Vitamins A and D

Mycoses induced by C.albicans or A.fumigatus can cause important host damage either by deficient or exaggerated immune response. Regulation of chemokine and cytokine signaling plays a crucial role for an adequate inflammation, which can be modulated by vitamins A and D. Non-coding RNAs (ncRNAs) as transcription factors or cis-acting antisense RNAs are known to be involved in gene regulation. However, the processes during fungal infections and treatment with vitamins in terms of therapeutic impact are unknown. We show that in monocytes both vitamins regulate ncRNAs involved in amino acid metabolism and immune system processes using comprehensive RNA-Seq analyses. Compared to protein-coding genes, fungi and bacteria induced an expression change in relatively few ncRNAs, but with massive fold changes of up to 4000. We defined the landscape of long-ncRNAs (lncRNAs) in response to pathogens and observed variation in the isoforms composition for several lncRNA following infection and vitamin treatment. Most of the involved antisense RNAs are regulated and positively correlated with their sense protein-coding genes. We investigated lncRNAs with stimulus specific immunomodulatory activity as potential marker genes: LINC00595, SBF2-AS1 (A.fumigatus) and RP11-588G21.2, RP11-394l13.1 (C.albicans) might be detectable in the early phase of infection and serve as therapeutic targets in the future.

Plasticity-driven individualization of olfactory coding in mushroom body output neurons

Although all sensory circuits ascend to higher brain areas where stimuli are represented in sparse, stimulus-specific activity patterns, relatively little is known about sensory coding on the descending side of neural circuits, as a network converges. In insects, mushroom bodies (MBs) have been an important model system for studying sparse coding in the olfactory system1–3, where this format is important for accurate memory formation4–6. In Drosophila, it has recently been shown that the 2000 Kenyon cells (KCs) of the MB converge onto a population of only 35 MB output neurons (MBONs), that fall into 22 anatomically distinct cell types7,8. Here we provide the first comprehensive view of olfactory representations at the fourth layer of the circuit, where we find a clear transition in the principles of sensory coding. We show that MBON tuning curves are highly correlated with one another. This is in sharp contrast to the process of progressive decorrelation of tuning in the earlier layers of the circuit2,9. Instead, at the population level, odor representations are reformatted so that positive and negative correlations arise between representations of different odors. At the single-cell level, we show that uniquely identifiable MBONs display profoundly different tuning across different animals, but tuning of the same neuron across the two hemispheres of an individual fly was nearly identical. Thus, individualized coordination of tuning arises at this level of the olfactory circuit. Furthermore, we find that this individualization is an active process that requires a learning-related gene, rutabaga. Ultimately, neural circuits have to flexibly map highly stimulus-specific information in sparse layers onto a limited number of different motor outputs. The reformatting of sensory representations we observe here may mark the beginning of this sensory-motor transition in the olfactory system.

Distinct MEG correlates of conscious experience, perceptual reversals and stabilization during binocular rivalry

During binocular rivalry, visual perception alternates spontaneously between two different monocular images. Such perceptual reversals are slowed or halted if stimuli are presented intermittently with inter-stimulus intervals larger than ~400ms — a phenomenon called stabilization. Often, the neural correlates of reversal and stabilization are studied separately, and both phenomena in turn are studied separately from the neural correlates of conscious perception. To distinguish the neural correlates of perceptual content, stabilization and reversal, we recorded MEG signals associated with each in the same group of healthy humans observing repeated trials of intermittent presentation of a dichoptic stimulus. Perceptual content correlated mainly with modulation of stimulus-specific activity in occipital/temporal areas 150–270ms after stimulus onset, possibly reflecting inhibition of the neural populations representing the suppressed image. Stability of perception reflected a gradual build-up of this modulation across at least 10 trials and was also, to some extent, associated with parietal activity 40–90ms and 220–270ms after stimulus onset. Perceptual reversals, in contrast, were associated with parietal (150–270ms) and temporal (150–210ms) activity on the trial before the reversal and a gradual change in perception-specific activity in occipital (150–270ms) and temporal (220–420ms) areas across at least 10 trials leading up to a reversal. Mechanistically, these findings suggest that stability of perception during rivalry is maintained by modulation of activity related to the two monocular images, and gradual adaptation of neuronal populations leads to instability that is eventually resolved by signals from parietal and late sensory cortices.

Flow of cortical activity underlying a tactile decision in mice.

Perceptual decisions involve distributed cortical activity. Does information flow sequentially from one cortical area to another, or do networks of interconnected areas contribute at the same time? Here we delineate when and how activity in specific areas drives a whisker-based decision in mice. A short-term memory component temporally separated tactile "sensation" and "action" (licking). Using optogenetic inhibition (spatial resolution, 2 mm; temporal resolution, 100 ms), we surveyed the neocortex for regions driving behavior during specific behavioral epochs. Barrel cortex was critical for sensation. During the short-term memory, unilateral inhibition of anterior lateral motor cortex biased responses to the ipsilateral side. Consistently, barrel cortex showed stimulus-specific activity during sensation, whereas motor cortex showed choice-specific preparatory activity and movement-related activity, consistent with roles in motor planning and movement. These results suggest serial information flow from sensory to motor areas during perceptual decision making.

Memory Consolidation by Replay of Stimulus-Specific Neural Activity

Memory consolidation transforms initially labile memory traces into more stable representations. One putative mechanism for consolidation is the reactivation of memory traces after their initial encoding during subsequent sleep or waking state. However, it is still unknown whether consolidation of individual memory contents relies on reactivation of stimulus-specific neural representations in humans. Investigating stimulus-specific representations in humans is particularly difficult, but potentially feasible using multivariate pattern classification analysis (MVPA). Here, we show in healthy human participants that stimulus-specific activation patterns can indeed be identified with MVPA, that these patterns reoccur spontaneously during postlearning resting periods and sleep, and that the frequency of reactivation predicts subsequent memory for individual items. We conducted a paired-associate learning task with items and spatial positions and extracted stimulus-specific activity patterns by MVPA in a simultaneous electroencephalography and functional magnetic resonance imaging (fMRI) study. As a first step, we investigated the amount of fMRI volumes during rest that resembled either one of the items shown before or one of the items shown as a control after the resting period. Reactivations during both awake resting state and sleep predicted subsequent memory. These data are first evidence that spontaneous reactivation of stimulus-specific activity patterns during resting state can be investigated using MVPA. They show that reactivation occurs in humans and is behaviorally relevant for stabilizing memory traces against interference. They move beyond previous studies because replay was investigated on the level of individual stimuli and because reactivations were not evoked by sensory cues but occurred spontaneously.

Identification and visualization of stimulus-specific transcriptional activity in cardiac hypertrophy in mice

Identification of specific signaling pathways for cardiac hypertrophy in living animals is challenging because no methods have been established to directly observe sequential molecular signaling events at the transcriptional level during pathogenesis. Here, our aim was to develop a useful method for monitoring the specific signaling pathways involved in the development of cardiac hypertrophy in vivo. Expression profiling of the left ventricle by microarray was performed in 2 different mouse models of cardiac hypertrophy: mechanical pressure overload by transverse aortic constriction (TAC) and neurohumoral activation by angiotensin II (Ang II) infusion. To annotate the information on transcription factor-binding sites, we collected promoter sequences and identified significantly frequent transcription factor-binding sites in the promoter regions of coregulated genes from both models (P < 0.05, binomial probability). Finally, we injected a firefly luciferase vector plasmid containing each transcription factor-binding site into the left ventricle in both models. In the TAC and Ang II models, we selected 379 and 12 upregulated genes, respectively. Twenty binding sites for transcription factors, including activator protein 4, were identified in the TAC model, and 4 sites for transcription factors, including ecotropic viral integration 1, were identified in the Ang II model. GATA-binding sites were noted in both models of cardiac hypertrophy. Using the firefly luciferase reporter, we demonstrated the enhancement of transcriptional activity during the progression of cardiac hypertrophy using in vivo imaging in live mice. These results suggested that our approach was useful for the identification of unique transcription factors that characterize different models of cardiac hypertrophy in vivo.

Identifying post-translational modifications of NEMO by tandem mass spectrometry after high affinity purification

An integral component of NF-κB signalling is NEMO, NF-κB essential modulator, a regulatory protein of the IκB kinase (IKK) complex. Post-translational modifications of NEMO, including phosphorylation, SUMOylation, and ubiquitination are critical events during stimuli induced NF-κB activation. Here we demonstrate a method to detect post-translational modifications of NEMO using cells stably expressing polyhistidine tagged NEMO which allows for high-affinity purification of NEMO following rapid denaturing lysis and characterization by MS/MS. We identified a previously uncharacterized basal phosphorylation of NEMO at Serine 387 and tested the biological significance of this phosphorylation through a somatic genetic complementation analysis using the NEMO mutants S387A, S388D, and P388I in 1.3E2 NEMO-deficient murine pre-B cells. NF-κB signalling induced by bacterial lipopolysaccharide, Interleukin-1ß or the DNA damaging agent etoposide was not perturbed by these mutations of NEMO. Thus, S387 phosphorylation of NEMO is not a general requirement to mediate efficient NF-κB signalling and therefore may have cell type and/or stimulus-specific activity in vivo.

Retrieval from the Brain's Perspective

Retrieval from the Brain's Perspective

Temporal dynamics of stimulus-specific gamma-band activity components during auditory short-term memory

Recently we have demonstrated that during auditory short-term memory maintenance, gamma-band activity (GBA) components can be identified which are specific to the retained stimulus. These activations peaked in the middle of the delay phase between sample and test stimuli, and their magnitude during the final part of this period correlated with performance. However, using a constant delay duration did not allow to answer the question whether stimulus-specific GBA components represented responses to sample sounds or anticipatory activations preceding test stimuli. Here we addressed this unresolved issue by investigating the temporal dynamics of stimulus-specific GBA during two delay durations. Magnetoencephalogram was recorded in 18 adults during an auditory spatial short-term memory task involving lateralized sample stimuli presented with two different interaural time delays. Subjects had to decide whether test stimuli presented after retention phases of 800 or 1200 ms had the same lateralization as sample sounds. Statistical probability mapping served to identify oscillatory activations differentiating between the two sample sounds. We found stimulus-specific GBA components over posterior cortex peaking about 400 ms prior to the onset of test stimuli regardless of delay duration. Their magnitude correlated with task performance. In summary, stimulus-specific GBA components with a predictive power for short-term memory performance were observed in anticipation of test stimuli. They may reflect the preparatory activation of memory representations or the shifting of attention to the specific expected location of the test stimulus.

Stimulus specific activity patterns in the granule cell networks of mice

It has been speculated that the olfactory bulb encodes information in the form of stimulus specific activity patterns. One of the key features of this population activity is the emergence of odor-specific spatial patterns of mitral cell spiking over a time course of 200–800 ms following stimulus (-odor) onset. We are interested in understanding the mechanisms involved in establishing and maintaining these spatial patterns. Here, we investigated the temporal response characteristics of granule cell activity by imaging activity in populations of olfactory bulb cells following bulk loading of calcium dye in olfactory bulb slices. We found that granule cells show varied (ranging from 0–900 ms) but reliable activation latencies (std. dev. = 50 ms). Moreover, we found that these activity patterns played a significant role in the generation and the maintenance of reliable spike patterns in mitral cells. Experiments in which multiple glomeruli were stimulated showed that the latency of granule cell activity is input specific and that individual granule cells respond most reliably to specific temporal patterns of stimulation. These data suggest that glomerular (~stimulus) identity is encoded in the form of latencies of granule cells activity, which in turn results in distinct stimulus specific changes in the pattern of mitral cell activity.

ERP correlates of the bilateral redundancy gain for words

Neurophysiological correlates of hemispheric asymmetry and interhemispheric interaction in lexical processing were investigated in a lexical decision task with tachistoscopic stimulus presentation either unilaterally, to the right or left visual field, or bilaterally, with identical stimulus copies to each visual hemi-field. Behavioral data confirmed both right visual field advantage and bilateral redundancy gain for words but not for pronounceable orthographically regular pseudowords. ERPs showed a significant amplitude increase 160–200 after stimulus presentation specifically for words after bilateral redundant stimulation, which was present in the recordings from both hemispheres. Localization of cortical sources using minimum norm estimation indicated stronger cortical activity for words in temporal regions of both hemispheres after bilateral presentation compared with each of the unilateral stimulation conditions individually. Pseudoword presentation did not lead to a general increase of cortical activation in the bilateral condition compared with unilateral presentation. The specific activation increase for words in the bilateral redundant condition relative to unilateral stimulation and the absence of this effect for pseudowords, which became manifest in a significant interaction of the factors lexicality and presentation mode, is best explained by summation of neuronal activation from both hemispheres within distributed lexical circuits. Source estimation indicates that temporal areas, particularly in the left hemisphere, are the primary cortical loci where such stimulus-specific activity increases occurred.

Modeling metacontrast masking with varying target and mask durations

In metacontrast, a target is rendered invisible by a surrounding mask that appears after the target's offset, providing a tool for investigating temporal aspects of visual coding. Previous manipulations of target and mask duration have used constant stimulus intensity, so that longer-lasting stimuli appear brighter. When brightness is controlled by compensating longer duration with lower intensity, increasing target duration has little effect on U-shaped metacontrast, but increasing mask duration monotonically decreases target visibility when the mask follows a 10 msec target immediately. These results were simulated with four models: efficient masking (Francis), decaying-trace (Anbar & Anbar), two-channel (Weisstein, 1968), and lateral inhibition (Bridgeman). Using parameters in each model that had successfully simulated metacontrast in the past, the efficient masking model yielded a monotonically increasing function of visibility in as target duration increased, while the other models gave U-shaped functions. Testing the remaining models in the increasing mask duration experiment, the decaying-trace model gave an increasing function where the psychophysics showed a decreasing function, the two-channel model showed a plateau of high visibility at low mask duration while the psychophysical function began declining immediately, and the lateral inhibition model accurately simulated the results. We also tested a recurrent processing model (DiLollo, Enns & Rensink), which did well here but does not have the parameters to test the target-duration condition. The lateral inhibition model performed best overall, perhaps because it relies on distributed coding rather than discrete detectors to simulate target visibility. In a single layer of simulated neurons, each cell inhibits six near neighbors; secondary interactions spread stimulus-specific activity across the network.

Split-second sequential selective activation in human secondary visual cortex.

This work addressed early selection based on nonspatial visual features, using event-related potentials (ERPs) with high temporal resolution and dipole-source modeling. Subjects were presented rapid sequences of gratings varying in spatial frequency and orientation, and were instructed to attend to gratings with one spatial frequency and ignore those with another. Attention effects started at 120-msec latency as anterior positivity and proceeded as posterior negativity (200 msec) and anterior negativity (265 msec). Dipole-source modeling suggested that these effects reflect the sequential selective activation of, on average, posterior dorsal-medial, posterior ventral-lateral, and anterior medial cortical areas. In contrast, stimulus-specific activity was observed well before 100-msec latency and characterized by dipoles with locations significantly posterior to those of the attention-modulated activity. These results indicate that even with highly discriminable spatial frequencies, selection is not as early as before the 100-msec latency, unlike what is often found for location selection. It is also separated in time and anatomically from the earliest stimulus-specific cortical activity. Reducing discriminability of the selection feature resulted in longer selection latencies, becoming manifest only at 175 msec as an apparent combination of posterior and anterior negativities, and in an elevated criterion for overt responding.