Project acronym AXONGROWTH
Project Systematic analysis of the molecular mechanisms underlying axon growth during development and following injury
Researcher (PI) Oren Schuldiner
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.
Summary
Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym AXONSURVIVAL
Project Axon survival: the role of protein synthesis
Researcher (PI) Christine Elizabeth Holt
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary Neurons make long-distance connections with synaptic targets via axons. These axons survive throughout the lifetime of an organism, often many years in mammals, yet how axons are maintained is not fully understood. Recently, we provided in vivo evidence that local mRNA translation in mature axons is required for their maintenance. This new finding, along with in vitro work from other groups, indicates that promoting axonal protein synthesis is a key mechanism by which trophic factors act to prevent axon degeneration. Here we propose a program of research to investigate the importance of ribosomal proteins (RPs) in axon maintenance and degeneration. The rationale for this is fourfold. First, recent genome-wide studies of axonal transcriptomes have revealed that protein synthesis (including RP mRNAs) is the highest functional category in several neuronal types. Second, some RPs have evolved extra-ribosomal functions that include signalling, such as 67LR which acts both as a cell surface receptor for laminin and as a RP. Third, mutations in different RPs in vertebrates cause unexpectedly specific defects, such as the loss of optic axons. Fourth, preliminary results show that RP mRNAs are translated in optic axons in response to trophic factors. Collectively these findings lead us to propose that locally synthesized RPs play a role in axon maintenance through either ribosomal or extra-ribosomal function. To pursue this proposal, we will perform unbiased screens and functional assays using an array of experimental approaches and animal models. By gaining an understanding of how local RP synthesis contributes to axon survival, our studies have the potential to provide novel insights into how components conventionally associated with a housekeeping role (translation) are linked to axon degeneration. Our findings could provide new directions for developing therapeutic tools for neurodegenerative disorders and may have an impact on more diverse areas of biology and disease.
Summary
Neurons make long-distance connections with synaptic targets via axons. These axons survive throughout the lifetime of an organism, often many years in mammals, yet how axons are maintained is not fully understood. Recently, we provided in vivo evidence that local mRNA translation in mature axons is required for their maintenance. This new finding, along with in vitro work from other groups, indicates that promoting axonal protein synthesis is a key mechanism by which trophic factors act to prevent axon degeneration. Here we propose a program of research to investigate the importance of ribosomal proteins (RPs) in axon maintenance and degeneration. The rationale for this is fourfold. First, recent genome-wide studies of axonal transcriptomes have revealed that protein synthesis (including RP mRNAs) is the highest functional category in several neuronal types. Second, some RPs have evolved extra-ribosomal functions that include signalling, such as 67LR which acts both as a cell surface receptor for laminin and as a RP. Third, mutations in different RPs in vertebrates cause unexpectedly specific defects, such as the loss of optic axons. Fourth, preliminary results show that RP mRNAs are translated in optic axons in response to trophic factors. Collectively these findings lead us to propose that locally synthesized RPs play a role in axon maintenance through either ribosomal or extra-ribosomal function. To pursue this proposal, we will perform unbiased screens and functional assays using an array of experimental approaches and animal models. By gaining an understanding of how local RP synthesis contributes to axon survival, our studies have the potential to provide novel insights into how components conventionally associated with a housekeeping role (translation) are linked to axon degeneration. Our findings could provide new directions for developing therapeutic tools for neurodegenerative disorders and may have an impact on more diverse areas of biology and disease.
Max ERC Funding
2 426 573 €
Duration
Start date: 2013-03-01, End date: 2018-09-30
Project acronym AXPLAST
Project Deep brain imaging of cellular mechanisms of sensory processing and learning
Researcher (PI) Jan GRUNDEMANN
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Summary
Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Max ERC Funding
1 475 475 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BehavIndividuality
Project Uncovering the basis of behavioral individuality across developmental time-scales
Researcher (PI) Shay Stern
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary A fundamental question in biology is why different individuals show different behaviors. While individuality in behavior is usually explained by genetic heterogeneity or differences in environmental exposures, more recent studies have shown that stable behavioral variation is also observed among isogenic individuals that were raised in the same environment. However, this important and potentially conserved epigenetic source of individual-to-individual behavioral variation remains largely unexplored. I have recently developed a novel imaging setup, using C. elegans, that allowed for the first time to study behavioral individuality across the full development time of animals, at high spatiotemporal resolution and under tightly controlled environmental conditions (Stern et al. Cell 2017). By using this unique system I found that isogenic animals show long-term behavioral individuality that persists across all developmental stages, and was dependent on specific neuromodulators. In this proposal I suggest to study how behavioral individuality emerges across development from non-genetic differences among individuals. In particular, I plan to (i) identify neuronal circuits and variations therein that lead to different behavioral states among individuals by combining my established methods for longitudinal behavioral quantifications with cutting-edge neuronal imaging and molecular techniques; (ii) study the role of conserved epigenetic mechanisms in generating stable neuronal and behavioral variations by integrating high-throughput gene-expression, neuronal, and behavioral analyses in single animals; and (iii) explore how stressful conditions affect behavioral individuality. I hypothesize that stress may enhance variation as a population-level mechanism to diversify risk in the face of complex or unpredictable conditions. The proposed research will shed light on novel processes that establish and maintain inter-individual diversity in neuronal and behavioral patterns.
Summary
A fundamental question in biology is why different individuals show different behaviors. While individuality in behavior is usually explained by genetic heterogeneity or differences in environmental exposures, more recent studies have shown that stable behavioral variation is also observed among isogenic individuals that were raised in the same environment. However, this important and potentially conserved epigenetic source of individual-to-individual behavioral variation remains largely unexplored. I have recently developed a novel imaging setup, using C. elegans, that allowed for the first time to study behavioral individuality across the full development time of animals, at high spatiotemporal resolution and under tightly controlled environmental conditions (Stern et al. Cell 2017). By using this unique system I found that isogenic animals show long-term behavioral individuality that persists across all developmental stages, and was dependent on specific neuromodulators. In this proposal I suggest to study how behavioral individuality emerges across development from non-genetic differences among individuals. In particular, I plan to (i) identify neuronal circuits and variations therein that lead to different behavioral states among individuals by combining my established methods for longitudinal behavioral quantifications with cutting-edge neuronal imaging and molecular techniques; (ii) study the role of conserved epigenetic mechanisms in generating stable neuronal and behavioral variations by integrating high-throughput gene-expression, neuronal, and behavioral analyses in single animals; and (iii) explore how stressful conditions affect behavioral individuality. I hypothesize that stress may enhance variation as a population-level mechanism to diversify risk in the face of complex or unpredictable conditions. The proposed research will shed light on novel processes that establish and maintain inter-individual diversity in neuronal and behavioral patterns.
Max ERC Funding
1 375 000 €
Duration
Start date: 2019-12-01, End date: 2024-11-30
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 Brain circRNAs
Project Rounding the circle: Unravelling the biogenesis, function and mechanism of action of circRNAs in the Drosophila brain.
Researcher (PI) Sebastian Kadener
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Tight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain
Summary
Tight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain
Max ERC Funding
1 971 750 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Summary
Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Max ERC Funding
2 489 643 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
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 BRAINCANNABINOIDS
Project Understanding the molecular blueprint and functional complexity of the endocannabinoid metabolome in the brain
Researcher (PI) István Katona
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Summary
We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Max ERC Funding
1 638 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym BRAINCOMPATH
Project Mesoscale Brain Dynamics: Computing with Neuronal Pathways
Researcher (PI) Fritjof Helmchen
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Summary
Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Max ERC Funding
2 498 915 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
