suppression

Targeting disulfidptosis in cancer: mechanisms and preclinical translation

Project Summary Studying regulated cell death is critical for our understanding of cellular homeostasis and tumor suppression. We recently discovered disulfidptosis as a new form of regulated cell death induced by disulfide stress under NADPH-depleting conditions in SLC7A11-high cancer cells. However, in contrast to our deep understanding of other cell death modalities such as apoptosis and ferroptosis, the molecular and metabolic underpinnings of disulfidptosis, along with its therapeutic implications, remain largely unexplored. The objectives of this application are to elucidate the mechanisms underlying disulfidptosis and to therapeutically target this form of cell death in SLC7A11-high cancers. The proposed studies will make extensive use of human cancer cell lines and integrated human cellbased molecular analyses, including metabolomics, proteomics, CRISPR screening, and biochemical studies, to define the metabolic and signaling mechanisms governing disulfidptosis. In addition, select in vivo studies are incorporated in the therapeutic validation components of the project, where tumor growth response, systemic drug exposure and tolerability, tumor microenvironmental influences, and host immune/stromal interactions must be evaluated in an organismal context to ensure translational rigor. Alternative in vitro systems such as organoids may provide useful complementary information on tumor-intrinsic responses, but they cannot fully recapitulate the systemic metabolic stress, pharmacologic exposure, and organism-level therapeutic efficacy required for these studies. It is expected that our proposed studies will reveal novel mechanisms underlying disulfidptosis and identify effective therapies to induce this form of cell death in SLC7A11-high cancers. Our proposal is highly innovative because it focuses on a previously unexplored cell death pathway in cancer therapy. Our proposed studies will have significant impact on both our understanding of the fundamental mechanisms of disulfidptosis and our ability to target this cell death pathway in cancer treatment.

Targeting VIP–VPAC Signaling to Reverse Immune Exclusion and Enhance Immunotherapy Response in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that is largely unresponsive to chemotherapy and current immune checkpoint blockade drugs, highlighting a critical need for the development of innovative therapeutic strategies. This R01 proposal targets vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide overexpressed in PDAC, which signals through VIP receptors (VPAC) on cancer cells, T cells, and myeloid cells within the tumor microenvironment. Based on our recent success in developing selective and potent VPAC receptor antagonists, we hypothesize that blocking VPAC signaling will reverse immunosuppression in the PDAC TME by reducing immune checkpoint expression, enhancing chemokine-driven infiltration of cytotoxic T cells, and disrupting immunosuppressive interactions between T cells and myeloid cells, ultimately leading to durable anti-cancer immunity. We propose three specific aims to explore the immunosuppressive roles of VPAC signaling in PDAC. Aim 1 will identify the primary sources of VIP in PDAC tumors and characterize the effects of VPAC signaling on immune cell function and phenotype within the tumor microenvironment. Aim 2 will investigate how VPAC signaling influences immune cell migration into tumors by modulating chemokine receptors and directional signaling. Aim 3 will determine how VPAC signaling regulates interactions between T cells and immunosuppressive myeloid cells, particularly tumor-associated macrophages, and the resulting impact on anti-cancer immune responses and immunological memory. Our preliminary findings indicate that combined inhibition of VPAC signaling and PD-1 significantly enhances the regression of PDAC tumors in multiple mouse models, generating lasting protective immunity in cured mice without triggering autoimmune responses. We will use novel methods to pursue our aims, including inducible genetically engineered mouse models (GEMM) of PDAC, long-acting VPAC antagonists engineered with immunoglobulin Fc domains to improve their plasma half-life, and advanced microfluidics technologies to analyze immune cell movement within tumors. Animal experiments will be used to validate the translational potential of observations from in vitro organoids and microfluidic experiments. The GEMM and orthotopic mouse models of PDAC are necessary to provide critical insights into the 3-D structure of the TME and tumor regression in response to our novel immunotherapy. This research will be conducted by a multidisciplinary team with complementary expertise that will clarify the therapeutic potential of VPAC signaling inhibition in PDAC using sophisticated experimental tools and single-cell RNA sequencing. Ultimately, these findings could significantly improve the development of immunotherapeutic strategies for PDAC, potentially enhancing patient outcomes in pancreatic cancer and other malignancies expressing high VIP levels.

Th17 plasticity in rheumatoid arthritis

ABSTRACT The objective of this grant application is to explore the plasticity of Th17 in arthritis. Interleukin-17A (IL-17A) producing Th17 are present in the blood and synovium of patients with rheumatoid arthritis (RA). However, targeting of IL17A has been insufficient to control joint inflammation of RA patients. One potential scenario is that in the context of worsening RA joint inflammation, Th17 undergo conversion into pathogenic IL17A- negative cell populations, collectively called exTh17. The conversion of Th17 into exTh17 has been documented in the context of neuroinflammation, colitis, and infection. However, the occurrence of Th17 plasticity in autoimmune arthritis and its potential role in perpetuating synovial inflammation has remained mostly unexplored. We generated a novel fate-mapping mouse model of autoimmune arthritis, which allows to follow the conversion of Th17 into exTh17, and collected preliminary data suggesting that Th17 undergo significant loss of IL17A expression and conversion into exTh17 in the context of synovial inflammation. We also identified exTh17 signatures which might help exTh17 perpetuate joint inflammation despite their loss of IL17A expression. Here our objective is to further elucidate intrinsic (Aim 1) and extrinsic (Aim 2) mechanism of Th17-exTh17 conversion and exTh17-mediated joint inflammation, and explore the potential role of exTh17 in RA interstitial lung disease (ILD, Aim 3) a feared and often untreatable complication of established RA. Our long-term goal is to leverage the knowledge of local immune cell phenotypes and how they change at various stages of disease to enable stage-specific and personalized therapies of RA which minimize non- specific immunosuppression.

Neural circuits for disinhibition in the cerebellum

ABSTRACT Our long-term goal is to understand how the cerebellum adapts and improves movements in response to motor errors. A critical component of this process is signaling from olivary climbing fibers that, by providing strong excitatory drive onto Purkinje cells, induces long-term synaptic plasticity to instantiate corrective adjustments in motor behavior. However, this signaling process is tightly regulated by molecular layer interneurons (MLIs). By strongly inhibiting Purkinje cells, MLIs oppose climbing fiber-driven excitation and gate the induction of corrective plasticity. Thus, for error-driven climbing fiber-induced plasticity and learning to occur effectively, Purkinje cells must undergo disinhibition through the suppression of MLI-mediated input. Notably, MLI ensembles are composed of several subtypes and have a highly structured interconnectivity and are responsive to convergent climbing fiber inputs, suggesting that climbing fiber synchrony- whose functional significance is poorly understood- can selectively engage MLI networks to alter the state of Purkinje cell inhibition. This engagement may balance inhibition and excitation of Purkinje cells during motor errors, creating a circuit mechanism conducive for the acquisition of adaptive learning. The objective of this proposal is to determine how distinct MLI circuits are organized to modulate Purkinje cell excitability through disinhibition in a context-dependent manner, enabling plasticity and learning in response to motor errors. We will employ functional recordings, circuit-targeted activity manipulations, and behavioral analysis to reveal how error-driven instructive signaling emerges from these circuits. In the first aim, we will use in vivo high-density electrophysiology to map functional interactions among MLIs, climbing fibers, and Purkinje cells in the flocculus during the vestibulo-ocular reflex. We will test whether, during motor errors, climbing fibers synchronize their firing to selectively engage disinhibition of Purkinje cells through MLI subtypes in adapting versus non-adapting contexts. In the second aim, we will combine acute slice recordings and molecular anatomy to define direct versus spillover climbing fiber synapses onto MLI subtypes. We will identify synaptic markers and measure climbing-fiber-evoked currents in MLI subtypes, revealing how structural connectivity supports rapid, subtype-specific circuit engagement. In the third aim, we will determine how long-range inputs to the inferior olive, specifically inhibitory projections from the vestibular nuclei, dynamically tune climbing fiber synchrony in vivo and thereby learning through differential engagement of disinhibitory MLI networks. Using functional recording and optogenetic manipulation during the vestibulo- ocular reflex performance, we will establish causal links between climbing fiber synchrony, MLI network state, and adaptive behavior. By fully understanding the logic of instructive signaling, emergent from cerebellar circuit organization and behavioral engagement, we will advance our knowledge of cerebellum-dependent learning processes and provide broader insights into the neural mechanisms of learning and adaptation more generally.

ATPase Chromatin Remodeling Complexes as Modulators of HIV-1 Latency and Therapeutic Targets

Abstract Significance: HIV persists in long-lived CD4⁺ T cell reservoirs despite suppressive ART, as integrated proviruses remain poised for reactivation. Chromatin remodeling is a central barrier to durable silencing, yet most studies have focused on SWI/SNF family members. The roles of non- SWI/SNF remodelers remain poorly defined, limiting our ability to rationally design host-directed “block-and-lock” cure strategies. Our unbiased shRNA screen of all 16 human remodeler ATPases identified EP400, CHD1, and CHD9 as repressors and INO80A, SMARCA5, and CHD2 as activators, establishing chromatin remodeling as a key determinant of HIV latency. Innovation: Our prior studies revealed that the p400 complex regulates HIV transcription through dual mechanisms: directly, by engaging Tat via the DMAP1 subunit to block Tat-TAR RNA interactions and restrict p-TEFb recruitment; and indirectly, by altering host transcriptional programs that control T cell activation states. Building on this mechanistic precedent and methodological platform, we now focus on INO80A, SMARCA5, CHD1, and CHD2, remodelers from distinct ATPase families that govern Tat-independent checkpoints at initiation, pause release, and elongation. Methodologically, we will apply TurboID-ChAP-MS (locus-specific proteomics), BEM-seq (single-nucleosome mapping), and degron-mediated acute depletion with ATPase-dead rescue to interrogate remodeler function with unprecedented resolution. Approach: Aim 1 will define the ATPase requirement and transcriptional checkpoints regulated by INO80A, SMARCA5, CHD1, and CHD2 using degron/CRISPR perturbations, ChIP-seq, nascent RNA profiling, and nucleosome mapping. Aim 2 will characterize remodeler-specific complexes and Tat dependence at the HIV promoter via TurboID proximity labeling integrated with chromatin affinity purification-mass spectrometry. Aim 3 will test combinatorial perturbations in Jurkat and primary CD4⁺ T cell latency models, including ART-suppressed donor cells, to identify synergistic “block-and-lock” strategies that enforce durable proviral silencing. Impact: By defining remodeler-specific mechanisms at discrete transcriptional checkpoints and leveraging their enzymatic, druggable activities, this work will establish chromatin remodeling as a therapeutic axis for durable HIV suppression and functional cure.

SUPPORT SERVICES FOR THE PREVENTION AND TREATMENT THROUGH A COMPREHENSIVE CARE CONTINUUM FOR HIV-AFFECTED ADOLESCENTS IN RESOURCE CONSTRAINED SETTINGS IMPLEMENTATION SCIENCE NETWORK

Support Services for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requires support for logistical and operational coordination, website and communication management, analytic and data management, infrastructure for emerging research, regulatory, and monitoring of research activities for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program. The NICHD and partner NIH Institutes anticipate funding 8 PATC3H-IN UG1 awards in Asia and throughout sub-Saharan Africa in 2023 through a cooperative agreement mechanism for interventions of high public health significance: The prevention of new HIV infections among adolescents at risk, and the identification of, linkage to and retention in care of, and long-term viral suppression among youth living with HIV in low-to-middle income countries with high HIV burden. The PATC3H-IN network will expand and/or improve on successes achieved by its predecessor, PATC3H, to new geographic settings and/or risk populations and stimulate much needed implementation science (IS) research in the prevention of new HIV infections among adolescents at risk and the identification of, and linkage and retention to care of and long-term viral suppression among youth living with HIV in low-to-middle income countries (LMICs). PATC3H-IN will establish a network of investigators with multidisciplinary expertise on the youth-specific PHCC and in IS research, whose mission will be to evaluate promising prevention innovations contextually and developmentally tailored for HIV uninfected at-risk youth, and treatment and care interventions for youth living with HIV which have demonstrated efficacy and/or effectiveness in adolescent or adult populations and to translate them into public health practices. The structure of PATC3H-IN will consist of multiple interdependent functional components: (1) Five Clinical Research Centers (CRC) awarded through the UG1 grant mechanism; (2) one Implementation Science Coordinating Center (ISCC) to be awarded through a UM2 grant mechanism in 2024; and (3) a Scientific Leadership Committee (SLC). The CRCs will conduct clinical research and clinical trials, including implementation, effectiveness, and hybrid implementation-effectiveness studies at their 8-or more participating Clinical Research Performance Sites (CRPS). The ISCC will establish infrastructure to support research education and capacity building across PATC3H-IN, as well as infrastructure for stakeholder engagement in and dissemination of findings from PATC3H-IN and advanced statistical modeling support across PATC3H-IN. The ISCC will also provide infrastructure for conducting foundational research to support the work of clinical sites, including possible modeling studies and translation projects, as well as national surveys, and/or systematic collection and analysis of relevant policies and laws. Lastly, the SLC will be responsible for PATC3H-IN governance, oversight, and coordination, and will develop and implement the network research agenda, convening working groups as needed, prioritizing emerging research projects, efficiently managing the development of clinical protocols, implementing and completing clinical trials, and ensuring timely publication and communication of results.

Continued HIV Production From Infected Macrophage In People On ART

PROJECT ABSTRACT After a few weeks of antiretroviral therapy (ART), HIV-1 RNA often decays to undetectable levels in blood. The initial decay is typically rapid due to the loss of short-lived, HIV-infected CD4+ T cells, but despite being adherent to ART, some people experience a subsequent period of slower decay and may require months to years to reach virologic suppression. The clinical significance of ‘slow decay’ of HIV-1 RNA after starting ART is currently unknown. Assessing the clinical significance of ‘slow decay virus’ requires identify the mechanisms generating it and exploring whether there is ongoing inflammation and neuronal damage in these people. There are three potential mechanisms that may generate ‘slow decay virus’ and they may have very different clinical implications. (1) Continued HIV-1 replication due to ineffective ART, poor ART adherence or drug- resistance. (2) Alternatively, ART could stop HIV-1 replication, but HIV-1 virions may continue to be produced by HIV-infected CD4+ T cells or (3) macrophage. Virus production without replication that emerges at the time of ART initiation is called primary nonsuppresible viremia (NSV) and is mechanistically distinct from secondary NSV observed in people who were previously suppressed. We recently examined four people who required approximately a year to become suppressed and found that ART stopped HIV-1 replication, but HIV-infected macrophage continued to produce substantial amounts of virus. These preliminary results are consistent with the long-held belief that after starting ART there is a period of rapid viral decay due to loss of HIV-infected CD4+ T cells, but some people have a subsequent period of slower decay due to continued virus production from long- lived, HIV-infected macrophage. The proposed work will expand on these observations and examine the mechanisms generating ‘slow decay virus’ in a much larger cohort of people on ART and explore the clinical implications of having ‘slow decay virus’ after starting ART (i.e. primary NSV). We will use existing, archived, longitudinal blood samples from 99 people in the MACS/WIHS Combined Cohort Study (MWCCS) who did not suppress HIV-1 RNA to undetectable levels by 6 months on ART (i.e. people with ‘slow decay virus’) and samples from 30 people who suppressed virus with typical, rapid kinetics. The proposed experiments will identify the mechanisms generating ‘slow decay virus’ during ART and the clinical implications of ‘slow decay virus’ (Aim 1). In our previous study, we also observed that ‘slow decay virus’ produced by macrophage often had nonsense/frameshift mutations in the HIV-1 vpr gene that may have promoted continued HIV-1 production from macrophage during ART. Specifically, we will explore whether ‘slow decay virus’ populations produced by macrophage have mutations in vpr or other genes that impact macrophage survival and/or HIV-1 production from infected macrophage (Aim 2). We will accomplish these aims using cutting-edge, but highly rigorous approaches. Accomplishing these aims will address clinical concerns about ‘slow decay virus’, the source of ‘slow decay virus’ as well as the role that Vpr plays in HIV-1 persistence and expression in macrophage during ART.

Circulating and Mucosal Predictors and Effects of Therapeutic Interleukin-23 Blockade in Crohn's Disease

PROJECT SUMMARY/ABSTRACT Since its discovery 20 years ago, the cytokine interleukin (IL)-23 has increasingly been implicated in the pathogenesis of immune mediated diseases, such as Crohn’s disease (CD). Consequently, four monoclonal antibodies that block IL-23 are currently approved CD therapies, including risankizumab. Although suppression of pathogenic Th17 cells has been widely cited as the mechanism by which IL-23 blockade controls disease, there is a paucity of data to indicate that this is how such therapy works, and a few other immune cell populations expressing the IL-23 receptor could instead be its target. We therefore propose to study how risankizumab affects not only Th17 cells, but also mucosa-associate invariant T (MAIT) cells γδ T cells and (in the colon) type 3 innate lymphoid cells (ILC3s). In addition to quantifying these cells, we will study their gene expression to detect phenotypic differences in treated patients, and in the case of T cells, track their clonal expansion and deletion through their unique T cell receptor sequences. In colon samples, we will use a combination of single cell sequencing of sort-enriched immune cell populations and spatial transcriptomics to characterize cells in situ, at the site of disease, and determine how IL-23 blockade affects their microenvironment in vivo. By contrasting results in patients who do or do not respond therapeutically to IL-23 blockade, we will reveal valuable insights into how this treatment succeeds or fails in CD, in the process identifying predictive biomarkers to guide treatment decisions, and potentially identifying future molecular targets with which to prevent treatment failure.

Magnetic resonance true temperature imaging with high spatial and temporal resolution

ABSTRACT The knowledge of temperature and temperature distribution within the brain can be critical to understanding the healthy and diseased brain, its response to acute injury, and in monitoring critically important thermal interventions. There are several temperature sensitive properties such relaxation rates and the proton resonance frequency shift (PRFS) that can be measured with magnetic resonance imaging (MRI) methods but these methods can only measure temperature change. The PRFS method, which provides the most accurate measurement of temperature change can only measure true tissue temperature if the starting true temperature distribution is known. Fortunately, MR spectroscopy (MRS) methods have been developed that show great promise in the measurement of true temperature. These methods rely on the detection of a temperature independent spectral peak of protons bound to carbon atoms in high concentration metabolites, such as N- acetylaspartate (NAA), creatine (Cr) and choline (Cho) which can be used as a reference for the temperature dependent spectral peak of water protons. Both single voxel spectroscopy (SVS) methods and MRS imaging (MRSI) methods have been described but are slow because of the long readout time needed to achieve adequate spectral resolution and the need to perform multiple averages due to the low signal being measured. Echo-planar spectroscopic imaging (EPSI) speeds up MRSI by interleaving an oscillating imaging gradient to spatially encode one of the imaging dimensions simultaneously with spectral readout. Unfortunately, SVS, MRSI, and even EPSI are unsuitable for clinical applications because of the low spatial resolution (voxel size 1 cm3) and temporal resolution (multiple minutes). The goal of this project is to develop an MRI technique that can measure true temperature in the whole brain at spatial and temporal resolutions that enable clinical utility for acutely assessing and longitudinally monitoring healthy and diseased brain tissue, and real time monitoring of thermal interventional therapies. This innovative true temperature measurement technique combines EPSI, for low resolution background field measurements, with PRFS for high spatial and temporal resolution water proton measurements. While conventional EPSI methods interleave volumetric acquisitions with and without water suppression, we propose an innovative modification to take advantage of the very strong water signal to obtain a very high resolution, dynamic method for true temperature measurements. The MRI pulse sequence will be refined, validated (Aim 1), applied to healthy subjects and post-surgery patients at risk for infections (Aim 2), and applied to essential tremor (ET) patients during the required delay between repeated focused ultrasound sonications (Aim 3). Successful completion of the aims of this study will result in a clinically practical method to obtain true temperature measurements in the brain with a spatial and temporal resolution sufficiently high to meet the needs of monitoring focal thermal therapy treatments as well as to provide true temperature measurements over the entire brain for assessment of the state of the brain with disease, infection, and injury.

Homeostatic Neural Responses to Photic Stimulation

This talk presents findings from open and closed-loop neural stimulation experiments using EEG. Fixed-frequency (10 Hz) stimulation revealed cross-cortical alpha power suppression post-stimulation, modulated by the difference between the individual's alpha frequency and the stimulation frequency. Closed-loop stimulation demonstrated phase-dependent effects: trough stimulation enhanced lower alpha activity, while peak stimulation suppressed high alpha to beta activity. These findings provide evidence for homeostatic mechanisms in the brain's response to photic stimulation, with implications for neuromodulation applications.

Seizure control by electrical stimulation: parameters and mechanisms

Seizure suppression by deep brain stimulation (DBS) applies high frequency stimulation (HFS) to grey matter to block seizures. In this presentation, I will present the results of a different method that employs low frequency stimulation (LFS) (1 to 10Hz) of white matter tracts to prevent seizures. The approach has been shown to be effective in the hippocampus by stimulating the ventral and dorsal hippocampal commissure in both animal and human studies respectively for mesial temporal lobe seizures. A similar stimulation paradigm has been shown to be effective at controlling focal cortical seizures in rats with corpus callosum stimulation. This stimulation targets the axons of the corpus callosum innervating the focal zone at low frequencies (5 to 10Hz) and has been shown to significantly reduce both seizure and spike frequency. The mechanisms of this suppression paradigm have been elucidated with in-vitro studies and involve the activation of two long-lasting inhibitory potentials GABAB and sAHP. LFS mechanisms are similar in both hippocampus and cortical brain slices. Additionally, the results show that LFS does not block seizures but rather decreases the excitability of the tissue to prevent seizures. Three methods of seizure suppression, LFS applied to fiber tracts, HFS applied to focal zone and stimulation of the anterior nucleus of the thalamus (ANT) were compared directly in the same animal in an in-vivo epilepsy model. The results indicate that LFS generated a significantly higher level of suppression, indicating LFS of white matter tract could be a useful addition as a stimulation paradigm for the treatment of epilepsy.

Diffuse coupling in the brain - A temperature dial for computation

The neurobiological mechanisms of arousal and anesthesia remain poorly understood. Recent evidence highlights the key role of interactions between the cerebral cortex and the diffusely projecting matrix thalamic nuclei. Here, we interrogate these processes in a whole-brain corticothalamic neural mass model endowed with targeted and diffusely projecting thalamocortical nuclei inferred from empirical data. This model captures key features seen in propofol anesthesia, including diminished network integration, lowered state diversity, impaired susceptibility to perturbation, and decreased corticocortical coherence. Collectively, these signatures reflect a suppression of information transfer across the cerebral cortex. We recover these signatures of conscious arousal by selectively stimulating the matrix thalamus, recapitulating empirical results in macaque, as well as wake-like information processing states that reflect the thalamic modulation of largescale cortical attractor dynamics. Our results highlight the role of matrix thalamocortical projections in shaping many features of complex cortical dynamics to facilitate the unique communication states supporting conscious awareness.

Immunosuppression for Parkinson's disease - a new therapeutic strategy?

Caroline Williams-Gray is a Principal Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and an honorary consultant neurologist specializing in Parkinson’s disease and movement disorders. She leads a translational research group investigating the clinical and biological heterogeneity of PD, with the ultimate goal of developing more targeted therapies for different Parkinson’s subtypes. Her recent work has focused on the theory that the immune system plays a significant role in mediating the heterogeneity of PD and its progression. Her lab is investigating this using blood and CSF -based immune markers, PET neuroimaging and neuropathology in stratified PD cohorts; and she is leading the first randomized controlled trial repurposing a peripheral immunosuppressive drug (azathioprine) to slow the progression of PD.

Universal function approximation in balanced spiking networks through convex-concave boundary composition

The spike-threshold nonlinearity is a fundamental, yet enigmatic, component of biological computation — despite its role in many theories, it has evaded definitive characterisation. Indeed, much classic work has attempted to limit the focus on spiking by smoothing over the spike threshold or by approximating spiking dynamics with firing-rate dynamics. Here, we take a novel perspective that captures the full potential of spike-based computation. Based on previous studies of the geometry of efficient spike-coding networks, we consider a population of neurons with low-rank connectivity, allowing us to cast each neuron’s threshold as a boundary in a space of population modes, or latent variables. Each neuron divides this latent space into subthreshold and suprathreshold areas. We then demonstrate how a network of inhibitory (I) neurons forms a convex, attracting boundary in the latent coding space, and a network of excitatory (E) neurons forms a concave, repellant boundary. Finally, we show how the combination of the two yields stable dynamics at the crossing of the E and I boundaries, and can be mapped onto a constrained optimization problem. The resultant EI networks are balanced, inhibition-stabilized, and exhibit asynchronous irregular activity, thereby closely resembling cortical networks of the brain. Moreover, we demonstrate how such networks can be tuned to either suppress or amplify noise, and how the composition of inhibitory convex and excitatory concave boundaries can result in universal function approximation. Our work puts forth a new theory of biologically-plausible computation in balanced spiking networks, and could serve as a novel framework for scalable and interpretable computation with spikes.

Perception during visual disruptions

Visual perception is perceived as continuous despite frequent disruptions in our visual environment. For example, internal events, such as saccadic eye-movements, and external events, such as object occlusion temporarily prevent visual information from reaching the brain. Combining evidence from these two models of visual disruption (occlusion and saccades), we will describe what information is maintained and how it is updated across the sensory interruption. Lina Teichmann will focus on dynamic occlusion and demonstrate how object motion is processed through perceptual gaps. Grace Edwards will then describe what pre-saccadic information is maintained across a saccade and how it interacts with post-saccadic processing in retinotopically relevant areas of the early visual cortex. Both occlusion and saccades provide a window into how the brain bridges perceptual disruptions. Our evidence thus far suggests a role for extrapolation, integration, and potentially suppression in both models. Combining evidence from these typically separate fields enables us to determine if there is a set of mechanisms which support visual processing during visual disruptions in general.

Unchanging and changing: hardwired taste circuits and their top-down control

The taste system detects 5 major categories of ethologically relevant stimuli (sweet, bitter, umami, sour and salt) and accordingly elicits acceptance or avoidance responses. While these taste responses are innate, the taste system retains a remarkable flexibility in response to changing external and internal contexts. Taste chemicals are first recognized by dedicated taste receptor cells (TRCs) and then transmitted to the cortex via a multi-station relay. I reasoned that if I could identify taste neural substrates along this pathway, it would provide an entry to decipher how taste signals are encoded to drive innate response and modulated to facilitate adaptive response. Given the innate nature of taste responses, these neural substrates should be genetically identifiable. I therefore exploited single-cell RNA sequencing to isolate molecular markers defining taste qualities in the taste ganglion and the nucleus of the solitary tract (NST) in the brainstem, the two stations transmitting taste signals from TRCs to the brain. How taste information propagates from the ganglion to the brain is highly debated (i.e., does taste information travel in labeled-lines?). Leveraging these genetic handles, I demonstrated one-to-one correspondence between ganglion and NST neurons coding for the same taste. Importantly, inactivating one ‘line’ did not affect responses to any other taste stimuli. These results clearly showed that taste information is transmitted to the brain via labeled lines. But are these labeled lines aptly adapted to the internal state and external environment? I studied the modulation of taste signals by conflicting taste qualities in the concurrence of sweet and bitter to understand how adaptive taste responses emerge from hardwired taste circuits. Using functional imaging, anatomical tracing and circuit mapping, I found that bitter signals suppress sweet signals in the NST via top-down modulation by taste cortex and amygdala of NST taste signals. While the bitter cortical field provides direct feedback onto the NST to amplify incoming bitter signals, it exerts negative feedback via amygdala onto the incoming sweet signal in the NST. By manipulating this feedback circuit, I showed that this top-down control is functionally required for bitter evoked suppression of sweet taste. These results illustrate how the taste system uses dedicated feedback lines to finely regulate innate behavioral responses and may have implications for the context-dependent modulation of hardwired circuits in general.

Meta-learning synaptic plasticity and memory addressing for continual familiarity detection

Over the course of a lifetime, we process a continual stream of information. Extracted from this stream, memories must be efficiently encoded and stored in an addressable manner for retrieval. To explore potential mechanisms, we consider a familiarity detection task where a subject reports whether an image has been previously encountered. We design a feedforward network endowed with synaptic plasticity and an addressing matrix, meta-learned to optimize familiarity detection over long intervals. We find that anti-Hebbian plasticity leads to better performance than Hebbian and replicates experimental results such as repetition suppression. A combinatorial addressing function emerges, selecting a unique neuron as an index into the synaptic memory matrix for storage or retrieval. Unlike previous models, this network operates continuously, and generalizes to intervals it has not been trained on. Our work suggests a biologically plausible mechanism for continual learning, and demonstrates an effective application of machine learning for neuroscience discovery.

Chemogenetic therapies for epilepsy: promises and challenges

Expression of Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. During my talk I will demonstrate that we obtained potent suppression of spontaneous epileptic seizures in mouse and a rat models for temporal lobe epilepsy using different DREADD ligands, up to one year after viral vector expression. The chemogenetic approach clearly outperforms the seizure-suppressing efficacy of currently existing anti-epileptic drugs. Besides the promises, I will also present some of the challenges associated with a potential chemogenetic therapy, including constitutive DREADD activity, tolerance effects, risk for toxicity, paradoxical excitatory effects in non-epileptic hippocampal tissue.

fMRI of cognitive reappraisal, acceptance, and suppression emotion regulation strategies in basic and clinically applied contexts

The ability to effectively regulate emotions is a fundamental skill related to physical and psychological health. In this talk, I will present behavioral and fMRI data from several different studies that examined cognitive reappraisal, acceptance, and suppression emotion regulation strategies in healthy controls participants and in the context of randomized trials of cognitive behavioral therapy, mindfulness- based stress reduction, and aerobic exercise as interventions for adults with anxiety disorders. We will also examine the implementation of different types of functional connectivity analytic approaches to probe intervention-related brain mechanism changes.

NMC4 Short Talk: Transient neuronal suppression for exploitation of new sensory evidence

Decision-making in noisy environments with constant sensory evidence involves integrating sequentially-sampled evidence, a strategy formalized by diffusion models which is supported by decades behavioral and neural findings. By contrast, it is unknown whether this strategy is also used during decision-making when the underlying sensory evidence is expected to change. Here, we trained monkeys to identify the dominant color of a dynamically refreshed checkerboard pattern that doesn't become informative until after a variable delay. Animals' behavioral responses were briefly suppressed after an abrupt change in evidence, and many neurons in the frontal eye field displayed a corresponding dip in activity at this time, similar to the dip frequently observed after stimulus onset. Generalized drift-diffusion models revealed that behavior and neural activity were consistent with a brief suppression of motor output without a change in evidence accumulation itself, in contrast to the popular belief that evidence accumulation is paused or reset. These results suggest that a brief interruption in motor preparation is an important strategy for dealing with changing evidence during perceptual decision making.

Expectation of self-generated sounds drives predictive processing in mouse auditory cortex

Sensory stimuli are often predictable consequences of one’s actions, and behavior exerts a correspondingly strong influence over sensory responses in the brain. Closed-loop experiments with the ability to control the sensory outcomes of specific animal behaviors have revealed that neural responses to self-generated sounds are suppressed in the auditory cortex, suggesting a role for prediction in local sensory processing. However, it is unclear whether this phenomenon derives from a precise movement-based prediction or how it affects the neural representation of incoming stimuli. We address these questions by designing a behavioral paradigm where mice learn to expect the predictable acoustic consequences of a simple forelimb movement. Neuronal recordings from auditory cortex revealed suppression of neural responses that was strongest for the expected tone and specific to the time of the sound-associated movement. Predictive suppression in the auditory cortex was layer-specific, preceded by the arrival of movement information, and unaffected by behavioral relevance or reward association. These findings illustrate that expectation, learned through motor-sensory experience, drives layer-specific predictive processing in the mouse auditory cortex.

Acetylcholine modulation of short-term plasticity is critical to reliable long-term plasticity in hippocampal synapses

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

Neural mechanisms for memory and emotional processing during sleep

The hippocampus and the amygdala are two structures required for emotional memory. While the hippocampus encodes the contextual part of the memory, the amygdala processes its emotional valence. During Non-REM sleep, the hippocampus displays high frequency oscillations called “ripples”. Our early work shows that the suppression of ripples during sleep impairs performance on a spatial task, underlying their crucial role in memory consolidation. We more recently showed that the joint amygdala-hippocampus activity linked to aversive learning is reinstated during the following Non-REM sleep epochs, specifically during ripples. This mechanism potentially sustains the consolidation of aversive associative memories during Non REM sleep. On the other hand, REM sleep is associated with regular 8 Hz theta oscillations, and is believed to play a role in emotional processing. A crucial, initial step in understanding this role is to unravel sleep dynamics related to REM sleep in the hippocampus-amygdala network

Optogenetic silencing of synaptic transmission with a mosquito rhodopsin

Long-range projections link distant circuits in the brain, allowing efficient transfer of information between regions and synchronization of distributed patterns of neural activity. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity, and optogenetic tools appear to be an obvious choice for such experiments. However, we and others have previously shown that commonly-used inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals. In my talk, I will present a new solution to this problem: a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3), which upon activation can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. The efficacy of eOPN3 in suppressing presynaptic release opens new avenues for functional interrogation of long-range neuronal circuits in vivo.

Translational upregulation of STXBP1 by non-coding RNAs as an innovative treatment for STXBP1 encephalopathy

Developmental and epileptic encephalopathies (DEEs) are a broad spectrum of genetic epilepsies associated with impaired neurological development as a direct consequence of a genetic mutation, in addition to the effect of the frequent epileptic activity on brain. Compelling genetic studies indicate that heterozygous de novo mutations represent the most common underlying genetic mechanism, in accordance with the sporadic presentation of DEE. De novo mutations may exert a loss-of-function (LOF) on the protein by decrementing expression level and/or activity, leading to functional haploinsufficiency. These diseases share several features: severe and frequent refractory seizures, diffusely abnormal background activity on EEG, intellectual disability often profound, and severe consequences on global development. One of major causes of early onset DEE are de novo heterozygous mutations in syntaxin-binding-protein-1 gene STXBP1, which encodes a membrane trafficking protein playing critical role in vesicular docking and fusion. LOF STXBP1 mutations lead to a failure of neurotransmitter secretion from synaptic vesicles. Core clinical features of STXBP1 encephalopathy include early-onset epilepsy with hypsarrhythmic EEG, or burst-suppression pattern, or multifocal epileptiform activity. Seizures are often resistant to standard treatments and patients typically show intellectual disability, mostly severe to profound. Additional neurologic features may include autistic traits, movement disorders (dyskinesia, dystonia, tremor), axial hypotonia, and ataxia, indicating a broader neurologic impairment. Patients with severe neuro-cognitive features but without epilepsy have been reported. Recently, a new class of natural and synthetic non-coding RNAs have been identified, enabling upregulation of protein translation in a gene-specific way (SINEUPs), without any increase in mRNA of the target gene. SINEUPs are translational activators composed by a Binding Domain (BD) that overlaps, in antisense orientation, to the sense protein-coding mRNA, and determines target selection; and an Effector Domain (ED), that is essential for protein synthesis up regulation. SINEUPs have been shown to restore the physiological expression of a protein in case of haploinsufficiency, without driving excessive overexpression out of the physiological range. This technology brings many advantages, as it mainly acts on endogenous target mRNAs produced in situ by the wild-type allele; this action is limited to mRNA under physiological regulation, therefore no off-site effects can be expected in cells and tissues that do not express the target transcript; by acting only on a posttranscriptional level, SINEUPs do not trigger hereditable genome editing. After bioinformatic analysis of the promoter region of interest, we designed SINEUPs with 3 different BD for STXBP1. Human neurons from iPSCs were treated and STXBP1 levels showed a 1.5-fold increase compared to the Negative control. RNA levels of STXBP1 after the administration of SINEUPs remained stable as expected. These preliminary results proved the SINEUPs potential to specifically increase the protein levels without impacting on the genome. This is an extremely flexible approach to target many developmental and epileptic encephalopathies caused by haploinsufficiency, and therefore to address these diseases in a more tailored and radical way.

A Cortical Circuit for Audio-Visual Predictions

Team work makes sensory streams work: our senses work together, learn from each other, and stand in for one another, the result of which is perception and understanding. Learned associations between stimuli in different sensory modalities can shape the way we perceive these stimuli (Mcgurk and Macdonald, 1976). During audio-visual associative learning, auditory cortex is thought to underlie multi-modal plasticity in visual cortex (McIntosh et al., 1998; Mishra et al., 2007; Zangenehpour and Zatorre, 2010). However, it is not well understood how processing in visual cortex is altered by an auditory stimulus that is predictive of a visual stimulus and what the mechanisms are that mediate such experience-dependent, audio-visual associations in sensory cortex. Here we describe a neural mechanism by which an auditory input can shape visual representations of behaviorally relevant stimuli through direct interactions between auditory and visual cortices. We show that the association of an auditory stimulus with a visual stimulus in a behaviorally relevant context leads to an experience-dependent suppression of visual responses in primary visual cortex (V1). Auditory cortex axons carry a mixture of auditory and retinotopically-matched visual input to V1, and optogenetic stimulation of these axons selectively suppresses V1 neurons responsive to the associated visual stimulus after, but not before, learning. Our results suggest that cross-modal associations can be stored in long-range cortical connections and that with learning these cross-modal connections function to suppress the responses to predictable input.

The When, Where and What of visual memory formation

The eyes send a continuous stream of about two million nerve fibers to the brain, but only a fraction of this information is stored as visual memories. This talk will detail three neurocomputational models that attempt an understanding how the visual system makes on-the-fly decisions about how to encode that information. First, the STST family of models (Bowman & Wyble 2007; Wyble, Potter, Bowman & Nieuwenstein 2011) proposes mechanisms for temporal segmentation of continuous input. The conclusion of this work is that the visual system has mechanisms for rapidly creating brief episodes of attention that highlight important moments in time, and also separates each episode from temporally adjacent neighbors to benefit learning. Next, the RAGNAROC model (Wyble et al. 2019) describes a decision process for determining the spatial focus (or foci) of attention in a spatiotopic field and the neural mechanisms that provide enhancement of targets and suppression of highly distracting information. This work highlights the importance of integrating behavioral and electrophysiological data to provide empirical constraints on a neurally plausible model of spatial attention. The model also highlights how a neural circuit can make decisions in a continuous space, rather than among discrete alternatives. Finally, the binding pool (Swan & Wyble 2014; Hedayati, O’Donnell, Wyble in Prep) provides a mechanism for selectively encoding specific attributes (i.e. color, shape, category) of a visual object to be stored in a consolidated memory representation. The binding pool is akin to a holographic memory system that layers representations of select latent representations corresponding to different attributes of a given object. Moreover, it can bind features into distinct objects by linking them to token placeholders. Future work looks toward combining these models into a coherent framework for understanding the full measure of on-the-fly attentional mechanisms and how they improve learning.

Cellular mechanisms behind stimulus evoked quenching of variability

A wealth of experimental studies show that the trial-to-trial variability of neuronal activity is quenched during stimulus evoked responses. This fact has helped ground a popular view that the variability of spiking activity can be decomposed into two components. The first is due to irregular spike timing conditioned on the firing rate of a neuron (i.e. a Poisson process), and the second is the trial-to-trial variability of the firing rate itself. Quenching of the variability of the overall response is assumed to be a reflection of a suppression of firing rate variability. Network models have explained this phenomenon through a variety of circuit mechanisms. However, in all cases, from the vantage of a neuron embedded within the network, quenching of its response variability is inherited from its synaptic input. We analyze in vivo whole cell recordings from principal cells in layer (L) 2/3 of mouse visual cortex. While the variability of the membrane potential is quenched upon stimulation, the variability of excitatory and inhibitory currents afferent to the neuron are amplified. This discord complicates the simple inheritance assumption that underpins network models of neuronal variability. We propose and validate an alternative (yet not mutually exclusive) mechanism for the quenching of neuronal variability. We show how an increase in synaptic conductance in the evoked state shunts the transfer of current to the membrane potential, formally decoupling changes in their trial-to-trial variability. The ubiquity of conductance based neuronal transfer combined with the simplicity of our model, provides an appealing framework. In particular, it shows how the dependence of cellular properties upon neuronal state is a critical, yet often ignored, factor. Further, our mechanism does not require a decomposition of variability into spiking and firing rate components, thereby challenging a long held view of neuronal activity.

Targeting the synapse in Alzheimer’s Disease

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

The many faces of KCC2 in the generation and suppression of seizures

KCC2, best known as the neuron-specific chloride extruder that sets the strength and polarity of GABAergic Cl-currents, is a multifunctional molecule which interacts with other ion-regulatory proteins and (structurally) with the neuronal cytoskeleton. Its multiple roles in the generation and suppression of seizures have been widely studied. In my talk, I will address some fundamental issues which are relevant in this field of research: What are EGABA shifts about? What is the role of KCC2 in shunting inhibition? What is meant by “the balance between excitation and inhibition” and, in this context, by the “NKCC1/KCC2 ratio”? Is down-regulation of KCC2 following neuronal trauma a manifestation of adaptive or maladaptive ionic plasticity? Under what conditions is K-Cl cotransport by KCC2 promoting seizures? Should we pay more attention to KCC2 as molecule involved in dendritic spine formation in brain areas such as the hippocampus? Most of these points are of potential importance also in the design of KCC2-targeting drugs and genetic manipulations aimed at combating seizures.

Synapse-specific direction selectivity in retinal bipolar cell axon terminals

The ability to encode the direction of image motion is fundamental to our sense of vision. Direction selectivity along the four cardinal directions is thought to originate in direction-selective ganglion cells (DSGCs), due to directionally-tuned GABAergic suppression by starburst cells. Here, by utilizing two-photon glutamate imaging to measure synaptic release, we reveal that direction selectivity along all four directions arises earlier than expected, at bipolar cell outputs. Thus, DSGCs receive directionally-aligned glutamatergic inputs from bipolar cell boutons. We further show that this bouton-specific tuning relies on cholinergic excitation and GABAergic inhibition from starburst cells. In this way, starburst cells are able to refine directional tuning in the excitatory visual pathway by modulating the activity of DSGC dendrites and their axonal inputs using two different neurotransmitters.

Untitled Seminar

Mammalian neonates are born immature. Thus mothers are equipped with innate motivation to nurture them. Moreover, in species that live in a family group, fathers and older siblings may also provide extensive care to the young. By studying those highly social species, including laboratory mice, common marmosets, and humans, we are trying to elucidate the neural mechanisms of parental care. Neuronal activity mapping and site-specific functional suppression in mice identified the central part of the medial preoptic area (cMPOA) as the hub of caregiving network for both mothers and fathers.Recent findings about the neural circuit and molecular signaling involved in caregiving motivation will be discussed.

Structured signals by a loss of structure: causes of burst-suppression EEG

Bernstein Conference 2024

Clear evidence in favor of adaptation and against temporally specific predictive suppression in monkey primary auditory cortex

COSYNE 2022

Input correlations impede suppression of chaos and learning in balanced rate networks

COSYNE 2022

Input correlations impede suppression of chaos and learning in balanced rate networks

COSYNE 2022

Mechanisms of surround facilitation and suppression to holographic perturbations

COSYNE 2022

Mechanisms of surround facilitation and suppression to holographic perturbations

COSYNE 2022

Recurrent suppression in visual cortex explained by a balanced network with sparse synaptic connections

COSYNE 2022

Recurrent suppression in visual cortex explained by a balanced network with sparse synaptic connections

COSYNE 2022

Regionally distinct striatal circuits support broadly opponent aspects of action suppression and production

COSYNE 2022

Regionally distinct striatal circuits support broadly opponent aspects of action suppression and production

COSYNE 2022

Mechanisms of contextual fear memory suppression and extinction by the Nucleus Reuniens-CA1 pathway

COSYNE 2023

Assessing the hyperexcitability of the epileptic brain by burst-suppression EEG reactivity

Assessment of the rat ischemic brain by burst-suppression EEG reactivity

Increasing cortico-subcortical connectivity predicts a bursting event during sevoflurane-induced burst suppression state in humans

Memory Suppression Relies on Targeted Representational Control of Individual Memories

mPGES-1 deficient rats lack LPS-inducible suppression of pulsatile secretion of luteinizing hormone

A neural mechanism involved in the motivational suppression of feeding by nociception

Suppression of mutant huntingtin improves cognitive symptoms in the R6/1 mouse model of Huntington’s disease

Surround suppression in mouse auditory cortex underlies auditory edge detection

A behavioral study to investigate flash suppression in pigeons

FENS Forum 2024

Chelerythrine chloride eliminates hypoxia-induced suppression of the AMPA neurotransmission in the visual retinocollicular pathway

FENS Forum 2024

Cortical layer-specific repetition suppression to faces in the fusiform face area

FENS Forum 2024

Gal3 suppression delays the motor coordination loss in the ataxic tambaleante mouse model

FENS Forum 2024

Modeling the effects of schizophrenia-related ion-channel encoding genes on P50 suppression

FENS Forum 2024

A physical impact to the cord leads to early massive depolarization sustained by chloride ions with transient reflex suppression

FENS Forum 2024

Rare tone suppression in inferior colliculus that depends on the relative predictability of sounds

FENS Forum 2024

Reduced routing efficiency in the right fronto-parietal attentional network during distractor suppression in mild cognitive impairment

FENS Forum 2024

The relationship between cortical somatosensory-auditory suppression and behaviour

FENS Forum 2024

Sequential appetite suppression by oral and visceral feedback to the brainstem

FENS Forum 2024

Brain-like visual surround suppression in generic CNNs: successes and limitations

Neuromatch 5

Visualizing surround suppression in deep convolutional neural networks

Neuromatch 5