Culture
culture
N/A
The successful candidate will work to develop specific solutions within the European project XTREME for: Mapping multichannel sound to an acoustic image stream with beamforming; Multimodal audio-visual detection and fusion for scene representation; Integration of 2D audio-visual reconstructed scene with 3D representations.
Pharmacological exploitation of neurotrophins and their receptors to develop novel therapeutic approaches against neurodegenerative diseases and brain trauma
Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.
Rett syndrome, MECP2 and therapeutic strategies
The development of the iPS cell technology has revolutionized our ability to study development and diseases in defined in vitro cell culture systems. The talk will focus on Rett Syndrome and discuss two topics: (i) the use of gene editing as an approach to therapy and (ii) the role of MECP2 in gene expression (i) The mutation of the X-linked MECP2 gene is causative for the disease. In a female patient, every cell has a wt copy that is, however, in 50% of the cells located on the inactive X chromosome. We have used epigenetic gene editing tools to activate the wt MECP2 allele on the inactive X chromosome. (ii) MECP2 is thought to act as repressor of gene expression. I will present data which show that MECP2 binds to Pol II and acts as an activator for thousands of genes. The target genes are significantly enriched for Autism related genes. Our data challenge the established model of MECP2’s role in gene expression and suggest novel therapeutic approaches.
Are integrative, multidisciplinary, and pragmatic models possible? The #PsychMapping experience
This presentation delves into the necessity for simplified models in the field of psychological sciences to cater to a diverse audience of practitioners. We introduce the #PsychMapping model, evaluate its merits and limitations, and discuss its place in contemporary scientific culture. The #PsychMapping model is the product of an extensive literature review, initially within the realm of sport and exercise psychology and subsequently encompassing a broader spectrum of psychological sciences. This model synthesizes the progress made in psychological sciences by categorizing variables into a framework that distinguishes between traits (e.g., body structure and personality) and states (e.g., heart rate and emotions). Furthermore, it delineates internal traits and states from the externalized self, which encompasses behaviour and performance. All three components—traits, states, and the externalized self—are in a continuous interplay with external physical, social, and circumstantial factors. Two core processes elucidate the interactions among these four primary clusters: external perception, encompassing the mechanism through which external stimuli transition into internal events, and self-regulation, which empowers individuals to become autonomous agents capable of exerting control over themselves and their actions. While the model inherently oversimplifies intricate processes, the central question remains: does its pragmatic utility outweigh its limitations, and can it serve as a valuable tool for comprehending human behaviour?
Conversations with Caves? Understanding the role of visual psychological phenomena in Upper Palaeolithic cave art making
How central were psychological features deriving from our visual systems to the early evolution of human visual culture? Art making emerged deep in our evolutionary history, with the earliest art appearing over 100,000 years ago as geometric patterns etched on fragments of ochre and shell, and figurative representations of prey animals flourishing in the Upper Palaeolithic (c. 40,000 – 15,000 years ago). The latter reflects a complex visual process; the ability to represent something that exists in the real world as a flat, two-dimensional image. In this presentation, I argue that pareidolia – the psychological phenomenon of seeing meaningful forms in random patterns, such as perceiving faces in clouds – was a fundamental process that facilitated the emergence of figurative representation. The influence of pareidolia has often been anecdotally observed in Upper Palaeolithic art examples, particularly cave art where the topographic features of cave wall were incorporated into animal depictions. Using novel virtual reality (VR) light simulations, I tested three hypotheses relating to pareidolia in the caves of Upper Palaeolithic cave art in the caves of Las Monedas and La Pasiega (Cantabria, Spain). To evaluate this further, I also developed an interdisciplinary VR eye-tracking experiment, where participants were immersed in virtual caves based on the cave of El Castillo (Cantabria, Spain). Together, these case studies suggest that pareidolia was an intrinsic part of artist-cave interactions (‘conversations’) that influenced the form and placement of figurative depictions in the cave. This has broader implications for conceiving of the role of visual psychological phenomena in the emergence and development of figurative art in the Palaeolithic.
Are integrative, multidisciplinary, and pragmatic models possible? The #PsychMapping experience
This presentation delves into the necessity for simplified models in the field of psychological sciences to cater to a diverse audience of practitioners. We introduce the #PsychMapping model, evaluate its merits and limitations, and discuss its place in contemporary scientific culture. The #PsychMapping model is the product of an extensive literature review, initially within the realm of sport and exercise psychology and subsequently encompassing a broader spectrum of psychological sciences. This model synthesizes the progress made in psychological sciences by categorizing variables into a framework that distinguishes between traits (e.g., body structure and personality) and states (e.g., heart rate and emotions). Furthermore, it delineates internal traits and states from the externalized self, which encompasses behaviour and performance. All three components—traits, states, and the externalized self—are in a continuous interplay with external physical, social, and circumstantial factors. Two core processes elucidate the interactions among these four primary clusters: external perception, encompassing the mechanism through which external stimuli transition into internal events, and self-regulation, which empowers individuals to become autonomous agents capable of exerting control over themselves and their actions. While the model inherently oversimplifies intricate processes, the central question remains: does its pragmatic utility outweigh its limitations, and can it serve as a valuable tool for comprehending human behaviour?
NOTE: DUE TO A CYBER ATTACK OUR UNIVERSITY WEB SYSTEM IS SHUT DOWN - TALK WILL BE RESCHEDULED
The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output and how neurons are integrated in the surrounding neuronal network. Accordingly, neurons with aberrant morphology have been associated with neurological disorders. Dysmorphic, enlarged neurons are, for example, a hallmark of focal epileptogenic lesions like focal cortical dysplasia (FCDIIb) and gangliogliomas (GG). However, the regulatory mechanisms governing the development of dendrites are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. Nevertheless, its function in neurons is unknown. We found that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ 3rd, order dendrites both in cultured neurons and living mice. Moreover, SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown causes a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission is unaffected. This mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations exhibit significant loss of SLK expression. To uncover the signaling cascades underlying the action of SLK, we combined phosphoproteomics, protein interaction screens and single cell RNA seq. Overall, our data identifies SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.
Internal representation of musical rhythm: transformation from sound to periodic beat
When listening to music, humans readily perceive and move along with a periodic beat. Critically, perception of a periodic beat is commonly elicited by rhythmic stimuli with physical features arranged in a way that is not strictly periodic. Hence, beat perception must capitalize on mechanisms that transform stimulus features into a temporally recurrent format with emphasized beat periodicity. Here, I will present a line of work that aims to clarify the nature and neural basis of this transformation. In these studies, electrophysiological activity was recorded as participants listened to rhythms known to induce perception of a consistent beat across healthy Western adults. The results show that the human brain selectively emphasizes beat representation when it is not acoustically prominent in the stimulus, and this transformation (i) can be captured non-invasively using surface EEG in adult participants, (ii) is already in place in 5- to 6-month-old infants, and (iii) cannot be fully explained by subcortical auditory nonlinearities. Moreover, as revealed by human intracerebral recordings, a prominent beat representation emerges already in the primary auditory cortex. Finally, electrophysiological recordings from the auditory cortex of a rhesus monkey show a significant enhancement of beat periodicities in this area, similar to humans. Taken together, these findings indicate an early, general auditory cortical stage of processing by which rhythmic inputs are rendered more temporally recurrent than they are in reality. Already present in non-human primates and human infants, this "periodized" default format could then be shaped by higher-level associative sensory-motor areas and guide movement in individuals with strongly coupled auditory and motor systems. Together, this highlights the multiplicity of neural processes supporting coordinated musical behaviors widely observed across human cultures.The experiments herein include: a motor timing task comparing the effects of movement vs non-movement with and without feedback (Exp. 1A & 1B), a transcranial magnetic stimulation (TMS) study on the role of the supplementary motor area (SMA) in transforming temporal information (Exp. 2), and a perceptual timing task investigating the effect of noisy movement on time perception with both visual and auditory modalities (Exp. 3A & 3B). Together, the results of these studies support the Bayesian cue combination framework, in that: movement improves the precision of time perception not only in perceptual timing tasks but also motor timing tasks (Exp. 1A & 1B), stimulating the SMA appears to disrupt the transformation of temporal information (Exp. 2), and when movement becomes unreliable or noisy there is no longer an improvement in precision of time perception (Exp. 3A & 3B). Although there is support for the proposed framework, more studies (i.e., fMRI, TMS, EEG, etc.) need to be conducted in order to better understand where and how this may be instantiated in the brain; however, this work provides a starting point to better understanding the intrinsic connection between time and movement
Epigenetic rewiring in Schinzel-Giedion syndrome
During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while some others can emerge in certain conditions, including other fate decisions or diseases, remains obscure. Schinzel-Giedion syndrome (SGS) is a rare disease with symptoms such as severe developmental delay, congenital malformations, progressive brain atrophy, intractable seizures, and infantile death. SGS is caused by mutations in the SETBP1 gene that results in its accumulation further leading to the downstream accumulation of SET. The oncoprotein SET has been found as part of the histone chaperone complex INHAT that blocks the activity of histone acetyltransferases suggesting that SGS may (i) represent a natural model of alternative chromatin regulation and (ii) offer chances to study downstream (mal)adaptive mechanisms. I will present our work on the characterization of SGS in appropriate experimental models including iPSC-derived cultures and mouse.
Cholesterol and matrisome pathways dysregulated in Alzheimer’s disease brain astrocytes and microglia
The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk." https://doi.org/10.1016/j.cell.2022.05.017
How can we shift research culture to drive Credibility in Neuroscience?
This webinar will demonstrate changes that are already happening at individual, institutional and funder level to shift research culture toward supporting credible research, and will allow attendees working in neuroscience to ask further questions to our speakers. Our panel of speakers, chaired by Ana Dorrego-Rivas: Emily Farran, Professor in Developmental Psychology and Academic Lead Research Culture and Integrity at the University of Surrey Rosa Sancho, Head of Research at Alzheimer's Research UK Sepideh Keshavarzi, Senior Research Fellow at the Sainsbury Wellcome Centre
Bridging the gap between artificial models and cortical circuits
Artificial neural networks simplify complex biological circuits into tractable models for computational exploration and experimentation. However, the simplification of artificial models also undermines their applicability to real brain dynamics. Typical efforts to address this mismatch add complexity to increasingly unwieldy models. Here, we take a different approach; by reducing the complexity of a biological cortical culture, we aim to distil the essential factors of neuronal dynamics and plasticity. We leverage recent advances in growing neurons from human induced pluripotent stem cells (hiPSCs) to analyse ex vivo cortical cultures with only two distinct excitatory and inhibitory neuron populations. Over 6 weeks of development, we record from thousands of neurons using high-density microelectrode arrays (HD-MEAs) that allow access to individual neurons and the broader population dynamics. We compare these dynamics to two-population artificial networks of single-compartment neurons with random sparse connections and show that they produce similar dynamics. Specifically, our model captures the firing and bursting statistics of the cultures. Moreover, tightly integrating models and cultures allows us to evaluate the impact of changing architectures over weeks of development, with and without external stimuli. Broadly, the use of simplified cortical cultures enables us to use the repertoire of theoretical neuroscience techniques established over the past decades on artificial network models. Our approach of deriving neural networks from human cells also allows us, for the first time, to directly compare neural dynamics of disease and control. We found that cultures e.g. from epilepsy patients tended to have increasingly more avalanches of synchronous activity over weeks of development, in contrast to the control cultures. Next, we will test possible interventions, in silico and in vitro, in a drive for personalised approaches to medical care. This work starts bridging an important theoretical-experimental neuroscience gap for advancing our understanding of mammalian neuron dynamics.
Root causes and possible solutions to academic bullying in higher education
Academic bullying is a serious issue that affects all disciplines and people of all levels of experience. To create a truly safe, productive, and vibrant environment in academia requires coordinated and collaborative input as well as the action of a variety of stakeholders, including scholarly communities, funding agencies, and institutions. This talk will focus on a framework of integrated responding, in which stakeholders as responsible and response-able parties could proactively collaborate and coordinate to reduce the incidence and consequences of academic bullying while at the same time building constructive academic cultures. The outcome of such a framework would be to create novel entities and actions that accelerate successful responses to academic bullying.
Cell-type specific genomics and transcriptomics of HIV in the brain
Exploration of genome organization and function in the HIV infected brain is critical to aid in the understanding and development of treatments for HIV-associated neurocognitive disorder (HAND). Here, we applied a multiomic approach, including single nuclei transcriptomics, cell-type specific Hi-C 3D genome mapping, and viral integration site sequencing (IS-seq) to frontal lobe tissue from HIV-infected individuals with encephalitis (HIVE) and without encephalitis (HIV+). We observed reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome with enrichment for regions containing interferon (IFN) pathway genes. 3D genome remodeling was associated with transcriptomic reprogramming, including down-regulation of cell adhesion and synapse-related functions and robust activation of IFN signaling and cell migratory pathways, and was recapitulated by IFN-g stimulation of cultured microglial cells. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 integration sites in the brain that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription, which was detected in 0.003% of all nuclei in HIVE brain, occurred in a subset of highly activated microglia that drove differential expression in HIVE. Thus, we observed a dynamic interrelationship of interferon-associated 3D genome and transcriptome remodeling with HIV integration and transcription in the brain.
How communication networks promote cross-cultural similarities: The case of category formation
Individuals vary widely in how they categorize novel phenomena. This individual variation has led canonical theories in cognitive and social science to suggest that communication in large social networks leads populations to construct divergent category systems. Yet, anthropological data indicates that large, independent societies consistently arrive at similar categories across a range of topics. How is it possible for diverse populations, consisting of individuals with significant variation in how they view the world, to independently construct similar categories? Through a series of online experiments, I show how large communication networks within cultures can promote the formation of similar categories across cultures. For this investigation, I designed an online “Grouping Game” to observe how people construct categories in both small and large populations when tasked with grouping together the same novel and ambiguous images. I replicated this design for English-speaking subjects in the U.S. and Mandarin-speaking subjects in China. In both cultures, solitary individuals and small social groups produced highly divergent category systems. Yet, large social groups separately and consistently arrived at highly similar categories both within and across cultures. These findings are accurately predicted by a simple mathematical model of critical mass dynamics. Altogether, I show how large communication networks can filter lexical diversity among individuals to produce replicable society-level patterns, yielding unexpected implications for cultural evolution. In particular, I discuss how participants in both cultures readily harnessed analogies when categorizing novel stimuli, and I examine the role of communication networks in promoting cross-cultural similarities in analogy-making as the key engine of category formation.
Malignant synaptic plasticity in pediatric high-grade gliomas
Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. Cell membrane protein capture (via biotinylation) and live imaging of pH sensitive GFP-tagged AMPAR subunits demonstrate an increase of calcium permeable channels at the tumors postsynaptic membrane in response to BDNF. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicates the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage normal mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.
Why is the suprachiasmatic nucleus such a brilliant circadian time-keeper?
Circadian clocks dominate our lives. By creating and distributing an internal representation of 24-hour solar time, they prepare us, and thereby adapt us, to the daily and seasonal world. Jet-lag is an obvious indicator of what can go wrong when such adaptation is disrupted acutely. More seriously, the growing prevalence of rotational shift-work which runs counter to our circadian life, is a significant chronic challenge to health, presenting as increased incidence of systemic conditions such as metabolic and cardiovascular disease. Added to this, circadian and sleep disturbances are a recognised feature of various neurological and psychiatric conditions, and in some cases may contribute to disease progression. The “head ganglion” of the circadian system is the suprachiasmatic nucleus (SCN) of the hypothalamus. It synchronises the, literally, innumerable cellular clocks across the body, to each other and to solar time. Isolated in organotypic slice culture, it can maintain precise, high-amplitude circadian cycles of neural activity, effectively, indefinitely, just as it does in vivo. How is this achieved: how does this clock in a dish work? This presentation will consider SCN time-keeping at the level of molecular feedback loops, neuropeptidergic networks and neuron-astrocyte interactions.
ReproNim: Towards a culture of more reproducible neuroimaging research
Given the intrinsically large and complex data sets collected in neuroimaging research, coupled with the extensive array of shared data and tools amassed in the research community, ReproNim seeks to lower the barriers for efficient: use of data; description of data and process; use of standards and best practices; sharing; and subsequent reuse of the collective ‘big’ data. Aggregation of data and reuse of analytic methods have become critical in addressing concerns about the replicability and power of many of today’s neuroimaging studies.
Making connections: how epithelial tissues guarantee folding
Tissue folding is a ubiquitous shape change event during development whereby a cell sheet bends into a curved 3D structure. This mechanical process is remarkably robust, and the correct final form is almost always achieved despite internal fluctuations and external perturbations inherent in living systems. While many genetic and molecular strategies that lead to robust development have been established, much less is known about how mechanical patterns and movements are ensured at the population level. I will describe how quantitative imaging, physical modeling and concepts from network science can uncover collective interactions that govern tissue patterning and shape change. Actin and myosin are two important cytoskeletal proteins involved in the force generation and movement of cells. Both parts of this talk will be about the spontaneous organization of actomyosin networks and their role in collective tissue dynamics. First, I will present how out-of-plane curvature can trigger the global alignment of actin fibers and a novel transition from collective to individual cell migration in culture. I will then describe how tissue-scale cytoskeletal patterns can guide tissue folding in the early fruit fly embryo. I will show that actin and myosin organize into a network that spans a domain of the embryo that will fold. Redundancy in this supracellular network encodes the tissue’s intrinsic robustness to mechanical and molecular perturbations during folding.
Using Human Stem Cells to Uncover Genetic Epilepsy Mechanisms
Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an increasingly utilized approach for neurological disease modeling with patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. Although most studies to date involve 2-D cultures of patient-derived neurons, brain organoids are increasingly being employed to explore genetic DEE mechanisms. We are applying this approach to understand PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome, Rett Syndrome (in collaboration with Ben Novitch at UCLA) and Protocadherin-19 Clustering Epilepsy (PCE). I will describe our findings of robust structural phenotypes in PMSE and PCE patient-derived brain organoid models, as well as functional abnormalities identified in fusion organoid models of Rett syndrome. In addition to showing epilepsy-relevant phenotypes, both 2D and brain organoid cultures offer platforms to identify novel therapies. We will also discuss challenges and recent advances in the brain organoid field, including a new single rosette brain organoid model that we have developed. The field is advancing rapidly and our findings suggest that brain organoid approaches offers great promise for modeling genetic neurodevelopmental epilepsies and identifying precision therapies.
Understanding Perceptual Priors with Massive Online Experiments
One of the most important questions in psychology and neuroscience is understanding how the outside world maps to internal representations. Classical psychophysics approaches to this problem have a number of limitations: they mostly study low dimensional perpetual spaces, and are constrained in the number and diversity of participants and experiments. As ecologically valid perception is rich, high dimensional, contextual, and culturally dependent, these impediments severely bias our understanding of perceptual representations. Recent technological advances—the emergence of so-called “Virtual Labs”— can significantly contribute toward overcoming these barriers. Here I present a number of specific strategies that my group has developed in order to probe representations across a number of dimensions. 1) Massive online experiments can increase significantly the amount of participants and experiments that can be carried out in a single study, while also significantly diversifying the participant pool. We have developed a platform, PsyNet, that enables “experiments as code,” whereby the orchestration of computer servers, recruiting, compensation of participants, and data management is fully automated and every experiment can be fully replicated with one command line. I will demonstrate how PsyNet allows us to recruit thousands of participants for each study with a large number of control experimental conditions, significantly increasing our understanding of auditory perception. 2) Virtual lab methods also enable us to run experiments that are nearly impossible in a traditional lab setting. I will demonstrate our development of adaptive sampling, a set of behavioural methods that combine machine learning sampling techniques (Monte Carlo Markov Chains) with human interactions and allow us to create high-dimensional maps of perceptual representations with unprecedented resolution. 3) Finally, I will demonstrate how the aforementioned methods can be applied to the study of perceptual priors in both audition and vision, with a focus on our work in cross-cultural research, which studies how perceptual priors are influenced by experience and culture in diverse samples of participants from around the world.
Capacitance clamp - artificial capacitance in biological neurons via dynamic clamp
A basic time scale in neural dynamics from single cells to the network level is the membrane time constant - set by a neuron’s input resistance and its capacitance. Interestingly, the membrane capacitance appears to be more dynamic than previously assumed with implications for neural function and pathology. Indeed, altered membrane capacitance has been observed in reaction to physiological changes like neural swelling, but also in ageing and Alzheimer's disease. Importantly, according to theory, even small changes of the capacitance can affect neuronal signal processing, e.g. increase network synchronization or facilitate transmission of high frequencies. In experiment, robust methods to modify the capacitance of a neuron have been missing. Here, we present the capacitance clamp - an electrophysiological method for capacitance control based on an unconventional application of the dynamic clamp. In its original form, dynamic clamp mimics additional synaptic or ionic conductances by injecting their respective currents. Whereas a conductance directly governs a current, the membrane capacitance determines how fast the voltage responds to a current. Accordingly, capacitance clamp mimics an altered capacitance by injecting a dynamic current that slows down or speeds up the voltage response (Fig 1 A). For the required dynamic current, the experimenter only has to specify the original cell and the desired target capacitance. In particular, capacitance clamp requires no detailed model of present conductances and thus can be applied in every excitable cell. To validate the capacitance clamp, we performed numerical simulations of the protocol and applied it to modify the capacitance of cultured neurons. First, we simulated capacitance clamp in conductance based neuron models and analysed impedance and firing frequency to verify the altered capacitance. Second, in dentate gyrus granule cells from rats, we could reliably control the capacitance in a range of 75 to 200% of the original capacitance and observed pronounced changes in the shape of the action potentials: increasing the capacitance reduced after-hyperpolarization amplitudes and slowed down repolarization. To conclude, we present a novel tool for electrophysiology: the capacitance clamp provides reliable control over the capacitance of a neuron and thereby opens a new way to study the temporal dynamics of excitable cells.
Untitled Seminar
Leah Krubitzer is a Distinguished Professor in the Department of Psychology at the University of California, Davis. Her graduate work focused on the evolution of visual cortex in primates, and she extended her research in Australia to include monotremes and marsupials. She has worked on the brains of over 45 different mammals. Her current research focuses on the impact of early experience and how culture impacts brain development. She also examines the evolution of sensory motor networks involved in manual dexterity, reaching and grasping in mammals. She received a MacArthur award for her work on evolution.
Using human pluripotent stem cells to model obesity in vitro
Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets.
Analogy as a Catalyst for Cumulative Cultural Evolution
Analogies, broadly defined, map novel concepts onto familiar concepts, making them essential for perception, reasoning, and communication. We argue that analogy-building served a critical role in the evolution of cumulative culture, by allowing humans to learn and transmit complex behavioural sequences that would otherwise be too cognitively demanding or opaque to acquire. The emergence of a protolanguage consisting of simple labels would have provided early humans with the cognitive tools to build explicit analogies and to communicate them to others. This focus on analogy-building can shed new light on the coevolution of cognition and culture, and addresses recent calls for better integration of the field of cultural evolution with cognitive science. This talk will address what cumulative cultural evolution is, how we define analogy-building, how analogy-building applies to cumulative cultural evolution, how analogy-building fits into language evolution, and the implications of analogy-building for causal understanding and cognitive evolution.
“Life in a Tight Spot: How Bacteria Move in Heterogeneous Media”
Bacterial motility is central to processes in agriculture, the environment, and medicine. While motility is typically studied in homogeneous environments, many bacterial habitats—e.g., soils, sediments, and biological gels/tissues—are heterogeneous porous media. Here, through studies of E. coli in transparent 3D porous media, we demonstrate that confinement in a heterogeneous medium fundamentally alters motility. In particular, we show how the paradigm of run-and-tumble motility is dramatically altered by pore-scale confinement, both for cells performing undirected motion and those performing chemotaxis, directed motion in response to a chemical stimulus. Our porous media also enable precisely structured multi-cellular communities to be 3D printed. Using this capability, we show how confinement-dependent chemotaxis enables populations to stabilize large-scale perturbations in their overall morphology. Together, our work thus reveals new principles to predict and control the behavior of bacteria, and active matter in general, in heterogeneous environments.
The social contract in miniature: Virtual Bargaining and the theory of joint action, meaning and the foundations of culture
How can people coordinate their actions or make joint decisions? One possibility is that each person attempts to predict the actions of the other(s), and best-responds accordingly. But this can lead to bad outcomes, and sometimes even vicious circularity. An alternative view is that each person attempts to work out what the two or more players would agree to do, if they were to bargain explicitly. If the result of such a "virtual" bargain is "obvious," then the players can simply play their respective roles in that bargain. I suggest that virtual bargaining is essential to genuinely social interaction (rather than viewing other people as instruments), and may even be uniquely human. This approach aims to respect methodological individualism, a key principle in many areas of social science, while explaining how human groups can, in a very real sense, be "greater" than the sum of their individual members.
Space for Thinking - Spatial Reference Frames and Abstract Concepts
People from cultures around the world tend to borrow from the domain of space to represent abstract concepts. For example, in the domain on time, we use spatial metaphors (e.g., describing the future as being in front and the past behind), accompany our speech with spatial gestures (e.g., gesturing to the left to refer to a past event), and use external tools that project time onto a spatial reference frame (e.g., calendars). Importantly, these associations are also present in the way we think and reason about time, suggesting that space and time are also linked in the mind. In this talk, I will explore the developmental origins and functional implications of these types of cross-dimensional associations. To start, I will discuss the roles that language and culture play in shaping how children in the US and India represent time. Next, I will use word learning and memory as test cases for exploring why cross-dimensional associations may be cognitively advantageous. Finally, I will talk about future directions and the practical implications for this line of work, with a focus on how encouraging spatial representations of abstract concepts could improve learning outcomes.
Cognition plus longevity equals culture: A new framework for understanding human brain evolution
Narratives of human evolution have focused on cortical expansion and increases in brain size relative to body size, but considered that changes in life history, such as in age at sexual maturity and thus the extent of childhood and maternal dependence, or maximal longevity, are evolved features that appeared as consequences of selection for increased brain size, or increased cognitive abilities that decrease mortality rates, or due to selection for grandmotherly contribution to feeding the young. Here I build on my recent finding that slower life histories universally accompany increased numbers of cortical neurons across warm-blooded species to propose a simpler framework for human evolution: that slower development to sexual maturity and increased post-maturity longevity are features that do not require selection, but rather inevitably and immediately accompany evolutionary increases in numbers of cortical neurons, thus fostering human social interactions and cultural and technological evolution as generational overlap increases.
Exploration of human neural phenotypic diversity through mixed-donor cultures of stem-cell derived NGN2-accelerated progenitors (SNaPs)
Modulation of C. elegans behavior by gut microbes
We are interested in understanding how microbes impact the behavior of host animals. Animal nervous systems likely evolved in environments richly surrounded by microbes, yet the impact of bacteria on nervous system function has been relatively under-studied. A challenge has been to identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. To accomplish these goals, we use an animal host — the roundworm C. elegans, which feeds on bacteria — in combination with its natural gut microbiome to identify inter-organismal signals driving host-microbe interactions and decision-making. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. Using this system, we discovered that commensal bacterial metabolites directly modulate nervous system function of their host. Beneficial gut microbes of the genus Providencia produce the neuromodulator tyramine in the C. elegans intestine. Using a combination of behavioral analysis, neurogenetics, metabolomics and bacterial genetics we established that bacterially produced tyramine is converted to octopamine in C. elegans, which acts directly in sensory neurons to reduce odor aversion and increase sensory preference for Providencia. We think that this type of sensory modulation may increase association of C. elegans with these microbes, increasing availability of this nutrient-rich food source for the worm and its progeny, while facilitating dispersal of the bacteria.
Motility-dependent pathogenicity of a spirochetal bacterium
Motility is a crucial virulence factor for many species of bacteria, but it is not fully understood how bacterial motility is practically involved in pathogenicity. This time I will give a talk on the association of motility with pathogenicity in the zoonotic spirochete bacterium Leptospira. Recently, we measured swimming force of individual leptospires using optical tweezers and found that they can generate ~30 times of the swimming force of E. coli. We also observed that leptospires increase the reversal frequency of swimming at the gel-liquid interface, resembling host dermis exposed to contaminated water (Abe et al., 2020, Sci Rep). These could be involved in percutaneous infection of the spirochete. We have shown that Leptospira not only swims in liquid but also moves over solid surfaces (Tahara et al., 2018, Sci Adv). We quantified the surface motility called “crawling” on cultured kidney tissues from various mammals, showing that pathogenic leptospires crawl over the tissue surfaces more persistently that non-pathogenic ones (Xu et al., 2020, Front Microbiol). I will discuss the spirochete motility related to pathogenicity from the biophysical viewpoint.
Carnosine negatively modulates pro-oxidant activities of M1 peripheral macrophages and prevents neuroinflammation induced by amyloid-β in microglial cells
Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.
The thalamus that speaks to the cortex: spontaneous activity in the developing brain
Our research team runs several related projects studying the cellular and molecular mechanisms involved in the development of axonal connections in the brain. In particular, our aim is to uncover the principles underlying thalamocortical axonal wiring, maintenance and ultimately the rewiring of connections, through an integrated and innovative experimental programme. The development of the thalamocortical wiring requires a precise topographical sorting of its connections. Each thalamic nucleus receives specific sensory information from the environment and projects topographically to its corresponding cortical. A second level of organization is achieved within each area, where thalamocortical connections display an intra-areal topographical organization, allowing the generation of accurate spatial representations within each cortical area. Therefore, the level of organization and specificity of the thalamocortical projections is much more complex than other projection systems in the CNS. The central hypothesis of our laboratory is that thalamocortical input influences and maintains the functional architecture of the sensory cortices. We also believe that rewiring and plasticity events can be triggered by activity-dependent mechanisms in the thalamus. Three major questions are been focused in the laboratory: i) the role of spontaneous patterns of activity in thalamocortical wiring and cortical development, ii) the role of the thalamus and its connectivity in the neuroplastic cortical changes following sensory deprivation, and iii) reprogramming thalamic cells for sensory circuit restoration. Within these projects we are using several experimental programmes, these include: optical imaging, manipulation of gene expression in vivo, cell and molecular biology, biochemistry, cell culture, sensory deprivation paradigms and electrophysiology. The results derived from our investigations will contribute to our understating of how reprogramming of cortical wiring takes place following brain damage and how cortical structure is maintained.
Functional characterization of human iPSC-derived neurons at single-cell resolution
Recent developments in induced pluripotent stem cell (iPSC) technology have enabled easier access to human cells in vitro. With increasing availability of human iPSC-derived neurons, both healthy and disease cell lines, screening compounds for neurodegenerative diseases on human cells can potentially be performed in the earlier stages of drug discovery. To accelerate the functional characterization of iPSC-derived neurons and the effect of compounds, reproducible and relevant results are necessary. In this webinar, the speakers will: Introduce high-resolution functional imaging of human iPSC-derived neurons Showcase how to extract functional features of hundreds of cells in a cell culture sample label-free Discuss electrophysiological parameters for characterizing the differences among several human neuronal cell lines
Chronic optogenetic stimulation has the potential to shape the collective activity of neuronal cell cultures
Bernstein Conference 2024
Artifact identification in transfer entropy connectivity inference of neuronal cultures
FENS Forum 2024
Caffeine treatment decreases MAO-B expression, neurite outgrowth, and neurite branching in immature rat primary neuronal cell cultures
FENS Forum 2024
Characterization of a new human co-culture model of endothelial cells, pericytes, and brain organoids in a microfluidic device
FENS Forum 2024
Computation with neuronal cultures: Effects of connectivity modularity on response separation and generalisation in simulations and experiments
FENS Forum 2024
Computer vision and image processing applications on astrocyte-glioma interactions in 3D cell culture
FENS Forum 2024
Deciphering developmental-aging mechanisms in cell culture: Aberrant ADNP cytoplasmic-nuclear crosstalk and NAP (davunetide) protection
FENS Forum 2024
Decoding neuronal identity maintenance and progenitor plasticity in extended brain organoid cultures
FENS Forum 2024
Development of an organ-on-chip platform for the co-culture of mouse organotypic brain slices with endothelial cells
FENS Forum 2024
Dynamic behaviour and functional organization of neuronal cultures grown in substrates with spatial anisotropies
FENS Forum 2024
Dynamics in human cortical cultures: A new era for individuals with epilepsy?
FENS Forum 2024
Effects of SARS-CoV-2 S1 protein and RNA vaccines on mixed neuronal-glial cell cultures
FENS Forum 2024
Effect of optogenetic modulation of neuronal ensembles in cultured neuronal networks
FENS Forum 2024
Exploring chemoconvulsant-induced non-coding RNA dynamics in rat primary cortical cell cultures
FENS Forum 2024
Exploring stimulation and plasticity in tailored neuronal cultures monitored on high-density multielectrode arrays
FENS Forum 2024
The functional transmission of information in a mixed-cultured neural network of chick and rat
FENS Forum 2024
Functional 3D in vitro coculture model for assessing human neuro-glioma interactions
FENS Forum 2024
hiPSC-derived dopaminergic and glutamatergic neurons of schizophrenia patients show neuronal aberrations in a co-culture model
FENS Forum 2024
Insulin action on the parameters of glutamatergic paired-pulse plasticity in cultured hippocampal neurons under hypoinsulinemia
FENS Forum 2024
Investigating the role of hyperphosphorylated tau in both neurodegenerative disease and glioblastoma using adult human organotypic slice cultures
FENS Forum 2024
Investigation of blood-brain barrier changes in acute pancreatitis: A cell culture and clinical study
FENS Forum 2024
Microglia activation is attenuated by dimethyltryptamine in primary cell cultures
FENS Forum 2024
Modelling synaptic tau and Aβ pathology in human organotypic brain slice cultures
FENS Forum 2024
Modulation of CaV1.2 currents tunes dendritic growth in cultured hippocampal neurons
FENS Forum 2024
Modulation of release of amyloid-β in live human brain slice cultures
FENS Forum 2024
Mouse hippocampal slice cultures as an ex vivo model for investigating SGSH enzyme replacement therapy in different brain cell types
FENS Forum 2024
Neuronal preservation and glial cell changes in human brain organotypic slice cultures
FENS Forum 2024
Neurotoxic effect of viral RNA-mimetic and alpha-synuclein in neuronal-glia co-cultures
FENS Forum 2024
N,N-Dimethyltryptamine has a protective effect against oxygen-glucose deprivation in a rat primary culture model of the blood-brain barrier
FENS Forum 2024
Reactive glia in culture boosts neurosphere formation by co-cultured non-reactive glia
FENS Forum 2024
Reservoir computing using cultured neuronal networks with modular topology
FENS Forum 2024
An in silico population of compartmental models of neurons from primary hippocampal cultures
FENS Forum 2024
Sub-toxic doses of glyphosate impair GABAergic synapses in cultured hippocampal neurons
FENS Forum 2024
Subcellular localization of the calcium channel Cav2.3 in cultured hippocampal neurons
FENS Forum 2024
It takes two - or three: Comparing human pluripotent stem cell derived glia-neuron co-cultures to neuron monoculture under basal and injury conditions
FENS Forum 2024
Unraveling neuroinflammation and cytoskeleton dynamics in brain ischemia: Insights from an oxygen-glucose deprivation model of stroke in organotypic hippocampal cultures for anti-inflammatory strategies
FENS Forum 2024
Unravelling microglia-specific contributions to neuronal network activity: Engineering a human stem cell-derived tri-culture on microelectrode arrays
FENS Forum 2024