Astrocytes as a mechanism for meta-plasticity and contextually-guided network function

Astrocytes are a ubiquitous and enigmatic type of non-neuronal cell and are found in the brain of all vertebrates. While traditionally viewed as being supportive of neurons, it is increasingly recognized that astrocytes may play a more direct and active role in brain function and neural computation. On account of their sensitivity to a host of physiological covariates and ability to modulate neuronal activity and connectivity on slower time scales, astrocytes may be particularly well poised to modulate the dynamics of neural circuits in functionally salient ways. In the current paper, we seek to capture these features via actionable abstractions within computational models of neuron-astrocyte interaction. Specifically, we engage how nested feedback loops of neuron-astrocyte interaction, acting over separated time-scales may endow astrocytes with the capability to enable learning in context-dependent settings, where fluctuations in task parameters may occur much more slowly than within-task requirements. We pose a general model of neuron-synapse-astrocyte interaction and use formal analysis to characterize how astrocytic modulation may constitute a form of meta-plasticity, altering the ways in which synapses and neurons adapt as a function of time. We then embed this model in a bandit-based reinforcement learning task environment, and show how the presence of time-scale separated astrocytic modulation enables learning over multiple fluctuating contexts. Indeed, these networks learn far more reliably versus dynamically homogeneous networks and conventional non-network-based bandit algorithms. Our results indicate how the presence of neuron-astrocyte interaction in the brain may benefit learning over different time-scales and the conveyance of task-relevant contextual information onto circuit dynamics.Comment: 42 pages, 14 figure

Simulation Tools for the Design of Virtual Training Environments

International audienceVirtual Reality (VR) for Education is spreading around and more and more training centers want to provide digital training, especially using VR technologies. The VR market is in full growth and many companies, startups and research teams are working on developing VR for Education on a large scale. Many domains are concerned by this learning digitalization, like science (Oliveira et al., 2019), military (Taupiac, 2018) and so on. The benefits of VR for education are numerous (Mano, 2019) and deeply investigated since the beginning of VR. There are many approaches in the process of training with VR, particularly since the commercialization of new VR headsets like HTC Vive™ and Oculus Rift™. Those headsets allow room scale tracking and are shipped with 3D space tracked controllers, granting a better user experience and a higher diversity in virtual training situations. New headsets are also affordable and so not only reserved for industrials, research or military, leading to new use of VR. In the VR industry, we have noticed some approaches used for the design of scenario. One classic approach is "serious game" that mainly consists in cloning classical educational games to VR, like point and clicks, 360° videos (Rupp et al., 2016) or dialog tree situations. The main interest of this category relies on existing projects and previous experiences with "standard serious games". The drawback is about the freshness of VR: it may not be suitable for those existing projects that were working nicely on a 2D screen. This kind of transposition could lead to atrocious user experiences and the underuse of the potential of VR. For educational purposes, other developers have followed another path: replicate reality. The main purpose is to provide situations that mimic real life situations. With this, training users with a high degree of realism eases skills transfer from VR to real situations. Realism can be achieved i

Virtual Interactive Tablet to Support Vocational Training in Immersive Environment

International audienceThis paper presents a tool designed to assist a virtual reality learner in a vocational training context. The benefits of VR are spreading outside the video-games and research field, leading the vocational education institutions to consider using this technology for training purposes. By simulating emblematic professional situations, teachers can train students in good conditions regarding safety, logistics and financial resources. In the French vocational training system, VR is just at its beginnings and the lack of experiments with this training context highlighted the need for new tools allowing teachers to use VR with their students. The work presented in this paper is part of a global project aiming to create, design and assess new VR tools and methodologies for this specific context. In order to guide, inform and assist the user, we are presenting a generic tool that can ease VR sessions by proposing embedded tools within easy reach of the immersed user, such as a camera, an inventory, a printer or stock management. This tool is a virtual tablet that can be grabbed by the immersed user allowing her/him to interact efficiently with the virtual environment

Experience-dependent resonance in amygdalocortical circuits supports fear memory retrieval following extinction

Theta range oscillations in the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) are associated with conditioned fear. Here, the authors use exogenous oscillatory stimulation of the BLA and mPFC in mice to determine the dynamic roles of theta-range oscillatory states across conditioned fear and extinction learning

Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.

N-methyl-D-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, D-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for D-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and D-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology

Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive function

Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive functionAstrocytes interact with neurons at the cellular level through modulation of synaptic formation, maturation, and function, but the impact of such interaction into behavior remains unclear. Here, we studied the dominant negative SNARE (dnSNARE) mouse model to dissect the role of astrocyte-derived signaling in corticolimbic circuits, with implications for cognitive processing. We found that the blockade of gliotransmitter release in astrocytes triggers a critical desynchronization of neural theta oscillations between dorsal hippocampus and prefrontal cortex. Moreover, we found a strong cognitive impairment in tasks depending on this network. Importantly, the supplementation with D-serine completely restores hippocampal-prefrontal theta synchronization and rescues the spatial memory and long-term memory of dnSNARE mice. We provide here novel evidence of long distance network modulation by astrocytes, with direct implications to cognitive function.Foundation for Science and Technology (FCT) project (PTDC/SAU-NSC/118194/ 2010) to V.M.S., S.G.G., G.T., M.M., J.S.R., J.S.C., J.F.O. and fellowships (SFRH/BD/ 89714/2012 to V.M.S., SFRH/BPD/97281/ 2013 to J.F.O., SFRH/BD/101298/2014 to S.G.G., IF/00328/2015 to JFO, IF/01079/ 2014 to LP); Marie Curie Fellowship FP7- PEOPLE-2010-IEF 273936 and BIAL Foundation Grants 207/14 to J.F.O. and 427/14 to LP; Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01- 0145-FEDER-000013); FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and National funds, through the FCT (POCI-01- 0145-FEDER-007038)info:eu-repo/semantics/publishedVersio

Regulating levels of the neuromodulator D-serine in human brain: structural insight into pLG72 and D-amino acid oxidase interaction

The human flavoenzyme D-amino acid oxidase (hDAAO) degrades the NMDA-receptor modulator D-serine in the brain. Whereas hDAAO has been extensively characterized, little is known about its main modulator pLG72, a small protein encoded by the primate-specific gene G72 that has been associated with schizophrenia susceptibility. pLG72 interacts with neosynthesized hDAAO, promoting its inactivation and degradation. In this work we used low-resolution techniques to characterize the surface topology of the hDAAO-pLG72 complex. By using limited proteolysis coupled to mass spectrometry we could map the exposed regions in the two proteins after complex formation and highlighted an increased sensitivity to proteolysis of hDAAO in complex with pLG72. Cross-linking experiments by using bis(sulfosuccinimidyl)suberate identified the single covalent bond between T182 in hDAAO and K62 in pLG72. In order to validate the designed mode of interaction, three pLG72 variants incrementally truncated at the C-terminus, in addition to a form lacking the 71 N-terminal residues, were produced. All variants were dimeric, folded, and interacted with hDAAO. The strongest decrease in affinity for hDAAO (as well as for the hydrophobic drug chlorpromazine) was apparent for the N-terminally deleted pLG7272-153 form, which lacked K62. On the other hand, eliminating the disordered C-terminal tail yielded a more stable pLG72 protein, improved the binding to hDAAO, although giving lower enzyme inhibition. Elucidation of the mode of hDAAO-pLG72 interaction now makes it possible to design novel molecules that, by targeting the protein complex, can be therapeutically advantageous for diseases related to impairment in D-serine metabolism. This article is protected by copyright. All rights reserved

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3

Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: NMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena. Experimental approach: Whole-cell patch-clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5-10 weeks) male Wistar rat hippocampus. Key results: Activation of A2A receptors with CGS 21680 (30 nM) consistently facilitated chemically-evoked NMDA receptor-currents (NMDA-PSCs) and afferent-evoked NMDA-currents (NMDA-EPSCs), an action prevented by an A2A receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H-89 (1 μM). These actions did not reflect facilitation in glutamate release since there was no change in NMDA-EPSCs paired pulse ratio. A2A receptor actions were lost in the presence of an open-channel NMDA receptor blocker, MK-801 (10 μM), but persisted in the presence of memantine, at a concentration (10 μM) known to preferentially block extrasynaptic NMDA receptors. Conclusion and implications: These results show that A2A receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non-pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.Work supported by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa 2020 (Programa Operacional Regional de Lisboa) from PORTUGAL 2020 and Fundação para a Ciência e Tecnologia, (FCT), by an FCT project (PTDC/DTP-FTO/3346/2014), and by a Twinning action (SynaNet) from the EU H2020 programme (project number: 692340). F.M.M. was in receipt of SFRH/BD/89582/2012 FTC fellowship, and D.M.R. is in receipt of a fellowship from Instituto de Medicina Molecular (IMM/BI/38-2017).info:eu-repo/semantics/publishedVersio