The Virtual Teacher (VT) Paradigm: Learning New Patterns of Interpersonal Coordination Using the Human Dynamic Clamp

The Virtual Teacher paradigm, a version of the Human Dynamic Clamp (HDC), is introduced into studies of learning patterns of inter-personal coordination. Combining mathematical modeling and experimentation, we investigate how the HDC may be used as a Virtual Teacher (VT) to help humans co-produce and internalize new inter-personal coordination pattern(s). Human learners produced rhythmic finger movements whilst observing a computer-driven avatar, animated by dynamic equations stemming from the well-established Haken-Kelso-Bunz (1985) and Schöner-Kelso (1988) models of coordination. We demonstrate that the VT is successful in shifting the pattern co-produced by the VT-human system toward any value (Experiment 1) and that the VT can help humans learn unstable relative phasing patterns (Experiment 2). Using transfer entropy, we find that information flow from one partner to the other increases when VT-human coordination loses stability. This suggests that variable joint performance may actually facilitate interaction, and in the long run learning. VT appears to be a promising tool for exploring basic learning processes involved in social interaction, unraveling the dynamics of information flow between interacting partners, and providing possible rehabilitation opportunities

Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach

In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a “learning signal” to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters

MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B

The heavily transcribed rDNA repeats that give rise to the ribosomal RNA are clustered in a unique chromatin structure, the nucleolus. Due to its highly repetitive nature and transcriptional activity, the nucleolus is considered a hotspot of genomic instability. Breaks in rDNA induce a transient transcriptional shut down to conserve energy and promote rDNA repair; however, how nucleolar chromatin is modified and impacts on rDNA repair is unknown. Here, we uncover that phosphorylation of serine 14 on histone H2B marks transcriptionally inactive nucleolar chromatin in response to DNA damage. We identified that the MST2 kinase localises at the nucleoli and targets phosphorylation of H2BS14p in an ATM-dependent manner. We show that establishment of H2BS14p is necessary for damage-induced rDNA transcriptional shut down and maintenance of genomic integrity. Ablation of MST2 kinase, or upstream activators, results in defective establishment of nucleolar H2BS14p, perturbed DNA damage repair, sensitisation to rDNA damage and increased cell lethality. We highlight the impact of chromatin regulation in the rDNA damage response and targeting of the nucleolus as an emerging cancer therapeutic approach

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis

RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis

Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C drives mesenchymal-to-amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC-mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that RASSF1C-induced amoeboid cells display increased expression of cancer stem-like markers such as CD133, ALDH1, and Nanog, and are accompanied by higher invasive potential in vitro and in vivo. Further, RASSF1C-induced amoeboid cells employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C-driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early-stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification

Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T-cells

Planar supported lipid bilayers (PSLBs) presenting T cell receptor (TCR) ligands and ICAM-1 induce budding of extracellular microvesicles enriched in functional TCR, defined here as synaptic ectosomes (SE), from helper T cells. SE bind peptide-MHC directly exporting TCR into the synaptic cleft, but incorporation of other effectors is unknown. Here, we utilized bead supported lipid bilayers (BSLB) to capture SE from single immunological synapses (IS), determined SE composition by immunofluorescence flow cytometry and enriched SE for proteomic analysis by particle sorting. We demonstrate selective enrichment of CD40L and ICOS in SE in response to addition of CD40 and ICOSL, respectively, to SLB presenting TCR ligands and ICAM-1. SE are enriched in tetraspanins, BST-2, TCR signalling and ESCRT proteins. Super-resolution microscopy demonstrated that CD40L is present in microclusters within CD81 defined SE that are spatially segregated from TCR/ICOS/BST-2. CD40L+ SE retain the capacity to induce dendritic cell maturation and cytokine production

Behavior Considered as an Enabling Constraint

Two fundamental challenges of contemporary neuroscience are to make sense of the scalar relations in the nervous system and to understand the way behavior emerges from these relations while at the same time affects them. In this paper, we analyze the notion of enabling constraint and the way it can frame the two kinds of relations involved in the challenges: of different neural scales (e.g., molecular scale, genetic scale, single-neurons, neural networks, etc.) and between neural systems and behavior. We think the notion of enabling constraint provides a promising alternative to other classic, mechanistic understandings of these relations and the different issues they raise for contemporary neuroscience

The dynamics of resting fluctuations in the brain: metastability and its dynamical cortical core

In the human brain, spontaneous activity during resting state consists of rapid transitions between functional network states over time but the underlying mechanisms are not understood. We use connectome based computational brain network modeling to reveal fundamental principles of how the human brain generates large-scale activity observable by noninvasive neuroimaging. We used structural and functional neuroimaging data to construct whole- brain models. With this novel approach, we reveal that the human brain during resting state operates at maximum metastability, i.e. in a state of maximum network switching. In addition, we investigate cortical heterogeneity across areas. Optimization of the spectral characteristics of each local brain region revealed the dynamical cortical core of the human brain, which is driving the activity of the rest of the whole brain. Brain network modelling goes beyond correlational neuroimaging analysis and reveals non-trivial network mechanisms underlying non-invasive observations. Our novel findings significantly pertain to the important role of computational connectomics in understanding principles of brain function.GD is supported by the ERC Advanced Grant DYSTRUCTURE (n. 295129), by the Spanish Research Project PSI2016-75688-P. MLK is supported by the ERC Consolidator Grant: CAREGIVING (n. 615539) and Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). VJ and GD are supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement n. 720270 (HBP SGA1). VJ and PR are supported by the James S. McDonnell Foundation (Brain Network Recovery Group JSMF22002082). VJ is supported by FHU EPINEXT [A*MIDEX project (ANR-11-IDEX-0001-02) funded by the ‘Investissements d’Avenir’ French Government]. PR is supported the German Ministry of Education and Research (US-German Collaboration in Computational Neuroscience 100258846 and Bernstein Focus State Dependencies of Learning 01GQ0971-5), the Max-Planck Society and funding from the European Union Horizon 2020 (ERC Consolidator grant BrainModes 683049)

Rethinking segregation and integration: contributions of whole-brain modelling

The brain regulates information flow by balancing the segregation and integration of incoming stimuli to facilitate flexible cognition and behaviour. The topological features of brain networks--in particular, network communities and hubs--support this segregation and integration but do not provide information about how external inputs are processed dynamically (that is, over time). Experiments in which the consequences of selective inputs on brain activity are controlled and traced with great precision could provide such information. However, such strategies have thus far had limited success. By contrast, recent whole-brain computational modelling approaches have enabled us to start assessing the effect of input perturbations on brain dynamics in silico.G.D. is supported by the European Research Council (ERC) Advanced grant: DYSTRUCTURE (no. 295129), by the Spanish Research Project SAF2010-16085, by the FP7-ICT BrainScales and by the Brain Network Recovery Group through the James S. McDonnell Foundation. G.T. is supported by the Paul Allen Family Foundation and by the James S. McDonnell Foundation. M.B. is supported by the Mind Science Foundation. M.L.K. is supported by the ERC Consolidator grant: CAREGIVING (no. 615539) and by the TrygFonden Charitable Foundation. The authors thank P. Maquet for agreeing to share the previously published sleep and wakefulness functional MRI data for the purposes of this article

Synaptic NMDA Receptor-Dependent Ca2+ Entry Drives Membrane Potential and Ca2+ Oscillations in Spinal Ventral Horn Neurons

During vertebrate locomotion, spinal neurons act as oscillators when initiated by glutamate release from descending systems. Activation of NMDA receptors initiates Ca(2+)-mediated intrinsic membrane potential oscillations in central pattern generator (CPG) neurons. NMDA receptor-dependent intrinsic oscillations require Ca(2+)-dependent K(+) (K(Ca)2) channels for burst termination. However, the location of Ca(2+) entry mediating K(Ca)2 channel activation, and type of Ca(2+) channel – which includes NMDA receptors and voltage-gated Ca(2+) channels (VGCCs) – remains elusive. NMDA receptor-dependent Ca(2+) entry necessitates presynaptic release of glutamate, implying a location at active synapses within dendrites, whereas VGCC-dependent Ca(2+) entry is not similarly constrained. Where Ca(2+) enters relative to K(Ca)2 channels is crucial to information processing of synaptic inputs necessary to coordinate locomotion. We demonstrate that Ca(2+) permeating NMDA receptors is the dominant source of Ca(2+) during NMDA-dependent oscillations in lamprey spinal neurons. This Ca(2+) entry is synaptically located, NMDA receptor-dependent, and sufficient to activate K(Ca)2 channels at excitatory interneuron synapses onto other CPG neurons. Selective blockade of VGCCs reduces whole-cell Ca(2+) entry but leaves membrane potential and Ca(2+) oscillations unaffected. Furthermore, repetitive oscillations are prevented by fast, but not slow, Ca(2+) chelation. Taken together, these results demonstrate that K(Ca)2 channels are closely located to NMDA receptor-dependent Ca(2+) entry. The close spatial relationship between NMDA receptors and K(Ca)2 channels provides an intrinsic mechanism whereby synaptic excitation both excites and subsequently inhibits ventral horn neurons of the spinal motor system. This places the components necessary for oscillation generation, and hence locomotion, at glutamatergic synapses