Project acronym ACTINIT
Project Brain-behavior forecasting: The causal determinants of spontaneous self-initiated action in the study of volition and the development of asynchronous brain-computer interfaces.
Researcher (PI) Aaron Schurger
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary "How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides ""when"" to perform an action, or ""whether"" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action ""now"", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect ""when"" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
Summary
"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides ""when"" to perform an action, or ""whether"" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action ""now"", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect ""when"" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
Max ERC Funding
1 338 130 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym ADOS
Project AMPA Receptor Dynamic Organization and Synaptic transmission in health and disease
Researcher (PI) Daniel Georges Gustave Choquet
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary AMPA glutamate receptors (AMPAR) play key roles in information processing by the brain as they mediate nearly all fast excitatory synaptic transmission. Their spatio-temporal organization in the post synapse with respect to presynaptic glutamate release sites is a key determinant in synaptic transmission. The activity-dependent regulation of AMPAR organization is at the heart of synaptic plasticity processes underlying learning and memory. Dysfunction of synaptic transmission - hence AMPAR organization - is likely at the origin of a number of brain diseases.
Building on discoveries made during my past ERC grant, our new ground-breaking objective is to uncover the mechanisms that link synaptic transmission with the dynamic organization of AMPAR and associated proteins. For this aim, we have assembled a team of neurobiologists, computer scientists and chemists with a track record of collaboration. We will combine physiology, cellular and molecular neurobiology with development of novel quantitative imaging and biomolecular tools to probe the molecular dynamics that regulate synaptic transmission.
Live high content 3D SuperResolution Light Imaging (SRLI) combined with electron microscopy will allow unprecedented visualization of AMPAR organization in synapses at the scale of individual subunits up to the level of intact tissue. Simultaneous SRLI and electrophysiology will elucidate the intricate relations between dynamic AMPAR organization, trafficking and synaptic transmission. Novel peptide- and small protein-based probes used as protein-protein interaction reporters and modulators will be developed to image and directly interfere with synapse organization.
We will identify new processes that are fundamental to activity dependent modifications of synaptic transmission. We will apply the above findings to understand the causes of early cognitive deficits in models of neurodegenerative disorders and open new avenues of research for innovative therapies.
Summary
AMPA glutamate receptors (AMPAR) play key roles in information processing by the brain as they mediate nearly all fast excitatory synaptic transmission. Their spatio-temporal organization in the post synapse with respect to presynaptic glutamate release sites is a key determinant in synaptic transmission. The activity-dependent regulation of AMPAR organization is at the heart of synaptic plasticity processes underlying learning and memory. Dysfunction of synaptic transmission - hence AMPAR organization - is likely at the origin of a number of brain diseases.
Building on discoveries made during my past ERC grant, our new ground-breaking objective is to uncover the mechanisms that link synaptic transmission with the dynamic organization of AMPAR and associated proteins. For this aim, we have assembled a team of neurobiologists, computer scientists and chemists with a track record of collaboration. We will combine physiology, cellular and molecular neurobiology with development of novel quantitative imaging and biomolecular tools to probe the molecular dynamics that regulate synaptic transmission.
Live high content 3D SuperResolution Light Imaging (SRLI) combined with electron microscopy will allow unprecedented visualization of AMPAR organization in synapses at the scale of individual subunits up to the level of intact tissue. Simultaneous SRLI and electrophysiology will elucidate the intricate relations between dynamic AMPAR organization, trafficking and synaptic transmission. Novel peptide- and small protein-based probes used as protein-protein interaction reporters and modulators will be developed to image and directly interfere with synapse organization.
We will identify new processes that are fundamental to activity dependent modifications of synaptic transmission. We will apply the above findings to understand the causes of early cognitive deficits in models of neurodegenerative disorders and open new avenues of research for innovative therapies.
Max ERC Funding
2 491 157 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ALS-Networks
Project Defining functional networks of genetic causes for ALS and related neurodegenerative disorders
Researcher (PI) Edor Kabashi
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Summary
Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym ARTTOUCH
Project Generating artificial touch: from the contribution of single tactile afferents to the encoding of complex percepts, and their implications for clinical innovation
Researcher (PI) Rochelle ACKERLEY
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.
Summary
Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.
Max ERC Funding
1 223 639 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym AstroWireSyn
Project Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity
Researcher (PI) Nathalie Rouach
Host Institution (HI) COLLEGE DE FRANCE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Summary
Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym BIOMOTIV
Project Why do we do what we do? Biological, psychological and computational bases of motivation
Researcher (PI) Mathias Pessiglione
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Summary
We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Max ERC Funding
1 346 000 €
Duration
Start date: 2011-03-01, End date: 2016-08-31
Project acronym Brain3.0
Project Invasive cognitive brain computer interfaces to enhance and restore attention: proof of concept and underlying cortical mechanisms.
Researcher (PI) Suliann Benhamed-Daghighi-Ardekani
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve:
1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance.
2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance.
3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects.
This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.
Summary
The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve:
1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance.
2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance.
3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects.
This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.
Max ERC Funding
1 997 748 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym BrainDyn
Project Tracking information flow in the brain: A unified and general framework for dynamic communication in brain networks
Researcher (PI) Mathilde BONNEFOND
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The brain is composed of a set of areas specialized in specific computations whose outputs need to be transferred to other specialized areas for cognition to emerge. To account for context-dependent behaviors, the information has to be flexibly routed through the fixed anatomy of the brain. The aim of my proposal is to test a general framework for flexible communication between brain areas based on nested oscillations which I recently developed. The general idea is that internally-driven slow oscillations (<20Hz) either set-up or prevent the communication between brain areas. Stimulus-driven gamma oscillations (>30Hz), nested in the slow oscillations, can then be directed to task-relevant areas of the network. I plan to use a multimodal, multi-scale and transversal (human and monkey) approach in experiments manipulating visual processing, attention and memory to test core predictions of my framework. The theoretical approach and the methodological development used in my project will provide the basis for future fundamental and clinical research.
Summary
The brain is composed of a set of areas specialized in specific computations whose outputs need to be transferred to other specialized areas for cognition to emerge. To account for context-dependent behaviors, the information has to be flexibly routed through the fixed anatomy of the brain. The aim of my proposal is to test a general framework for flexible communication between brain areas based on nested oscillations which I recently developed. The general idea is that internally-driven slow oscillations (<20Hz) either set-up or prevent the communication between brain areas. Stimulus-driven gamma oscillations (>30Hz), nested in the slow oscillations, can then be directed to task-relevant areas of the network. I plan to use a multimodal, multi-scale and transversal (human and monkey) approach in experiments manipulating visual processing, attention and memory to test core predictions of my framework. The theoretical approach and the methodological development used in my project will provide the basis for future fundamental and clinical research.
Max ERC Funding
1 333 718 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym BRAINSTRUCT
Project Building up a brain: understanding how neural stem cell fate and regulation controls nervous tissue architecture
Researcher (PI) Jean Livet
Host Institution (HI) SORBONNE UNIVERSITE
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.
Summary
The brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.
Max ERC Funding
1 929 713 €
Duration
Start date: 2015-07-01, End date: 2021-06-30
Project acronym C.NAPSE
Project TOWARDS A COMPREHENSIVE ANALYSIS OF EXTRACELLULAR SCAFFOLDING AT THE SYNAPSE
Researcher (PI) Jean-Louis BESSEREAU
Host Institution (HI) UNIVERSITE LYON 1 CLAUDE BERNARD
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary Synaptic scaffolding molecules control the localization and the abundance of neurotransmitter receptors at the synapse, a key parameter to shape synaptic transfer function. Most characterized synaptic scaffolds are intracellular, yet a growing number of secreted proteins appear to organize the synapse from the outside of the cell. We recently demonstrated in C. elegans that an evolutionarily conserved protein secreted by motoneurons specifies the excitatory versus inhibitory identity of the postsynaptic domains at neuromuscular synapses. We propose to use this system as a genetically tractable paradigm to perform a comprehensive characterization of this unforeseen synaptic organization.
Specifically, this project will pursue 4 complementary aims:
1) Identify and characterize a comprehensive set of genes that organize and control the formation and maintenance of these scaffolds through a series of genetic screens based on the direct visualization of fluorescent acetylcholine and GABA receptors in living animals.
2) Solve the spatial synaptic organization of these scaffolds at a nanoscale resolution using super-resolutive and correlative light and electron microscopy, and analyze their dynamic behavior in vivo by implementing Single Particle Tracking imaging in living worms.
3) Decipher the role of the synaptomatrix in the organization of synaptic extracellular scaffolds and evaluate its functional contribution at the physiological and molecular levels using a candidate gene strategy and innovative imaging.
4) Analyze the formation and decline of these scaffolds at the lifetime scale and evaluate the role of synaptic activity and aging in these processes by taking advantage of the possibility to follow identified synapses over the entire life of C. elegans.
Using powerful genetics in combination with cutting-edge in vivo imaging and electrophysiology, we anticipate to identify new genes and new mechanisms at work to regulate normal and pathological synaptic function.
Summary
Synaptic scaffolding molecules control the localization and the abundance of neurotransmitter receptors at the synapse, a key parameter to shape synaptic transfer function. Most characterized synaptic scaffolds are intracellular, yet a growing number of secreted proteins appear to organize the synapse from the outside of the cell. We recently demonstrated in C. elegans that an evolutionarily conserved protein secreted by motoneurons specifies the excitatory versus inhibitory identity of the postsynaptic domains at neuromuscular synapses. We propose to use this system as a genetically tractable paradigm to perform a comprehensive characterization of this unforeseen synaptic organization.
Specifically, this project will pursue 4 complementary aims:
1) Identify and characterize a comprehensive set of genes that organize and control the formation and maintenance of these scaffolds through a series of genetic screens based on the direct visualization of fluorescent acetylcholine and GABA receptors in living animals.
2) Solve the spatial synaptic organization of these scaffolds at a nanoscale resolution using super-resolutive and correlative light and electron microscopy, and analyze their dynamic behavior in vivo by implementing Single Particle Tracking imaging in living worms.
3) Decipher the role of the synaptomatrix in the organization of synaptic extracellular scaffolds and evaluate its functional contribution at the physiological and molecular levels using a candidate gene strategy and innovative imaging.
4) Analyze the formation and decline of these scaffolds at the lifetime scale and evaluate the role of synaptic activity and aging in these processes by taking advantage of the possibility to follow identified synapses over the entire life of C. elegans.
Using powerful genetics in combination with cutting-edge in vivo imaging and electrophysiology, we anticipate to identify new genes and new mechanisms at work to regulate normal and pathological synaptic function.
Max ERC Funding
2 492 750 €
Duration
Start date: 2016-10-01, End date: 2022-09-30
