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 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: 2020-06-30
Project acronym C9ND
Project C9orf72-mediated neurodegeneration: mechanisms and therapeutics
Researcher (PI) Adrian Michael Isaacs
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat RNA is transcribed and accumulates in neuronal RNA aggregates, implicating RNA toxicity as a key pathogenic mechanism. However, the pathways that lead to neurodegeneration are unknown. My lab has made pioneering contributions to the understanding of C9orf72 FTD/ALS, and reported the first structure of the repeat RNA, and the first description of both sense and antisense RNA aggregates in patient brain. We have now developed new disease models that allow, for the first time, the dissection of RNA toxicity both in vivo and in sophisticated neuronal culture models. We have also used our knowledge of the repeat structure to identify novel small molecules that show very strong binding to the repeats. We will utilise our innovative disease models in a multidisciplinary approach to fully dissect the cellular pathways underlying C9orf72 repeat RNA toxicity in vivo, on a genome-wide scale. Altered RNA metabolism has been implicated in a wide range of neurodegenerative diseases, indicating that our findings will provide profound new insight into fundamental mechanisms of neuronal maintenance and survival. This research programme will also deliver a step change in our understanding of C9orf72 FTD/ALS pathogenesis and provide essential insight for the identification of small molecules with genuine therapeutic potential. RNA-mediated mechanisms are now known to be a common theme in neurodegeneration, suggesting these findings will have broad significance.
Summary
An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat RNA is transcribed and accumulates in neuronal RNA aggregates, implicating RNA toxicity as a key pathogenic mechanism. However, the pathways that lead to neurodegeneration are unknown. My lab has made pioneering contributions to the understanding of C9orf72 FTD/ALS, and reported the first structure of the repeat RNA, and the first description of both sense and antisense RNA aggregates in patient brain. We have now developed new disease models that allow, for the first time, the dissection of RNA toxicity both in vivo and in sophisticated neuronal culture models. We have also used our knowledge of the repeat structure to identify novel small molecules that show very strong binding to the repeats. We will utilise our innovative disease models in a multidisciplinary approach to fully dissect the cellular pathways underlying C9orf72 repeat RNA toxicity in vivo, on a genome-wide scale. Altered RNA metabolism has been implicated in a wide range of neurodegenerative diseases, indicating that our findings will provide profound new insight into fundamental mechanisms of neuronal maintenance and survival. This research programme will also deliver a step change in our understanding of C9orf72 FTD/ALS pathogenesis and provide essential insight for the identification of small molecules with genuine therapeutic potential. RNA-mediated mechanisms are now known to be a common theme in neurodegeneration, suggesting these findings will have broad significance.
Max ERC Funding
1 985 699 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym Clock Mechanics
Project Mechanosensation and the circadian clock: a reciprocal analysis
Researcher (PI) Joerg Albert
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time.
Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.
Summary
All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time.
Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.
Max ERC Funding
1 899 549 €
Duration
Start date: 2015-09-01, End date: 2021-08-31
Project acronym DEPICODE
Project Decoding the epigenetic signature of memory function in health and disease
Researcher (PI) André Fischer
Host Institution (HI) DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The emerging field of neuroepigenetics investigates processes such as histone-acetylation in the context of neuronal plasticity, memory function and brain diseases. My group has significantly contributed to this novel research field. It is however fair to say that the role of “epigenetics” in memory function is still met with some skepticism in the neurosciences, which is in part due to the fact that many of the current studies have been describing phenomena and mechanistic data to explain how epigenetic processes control memory function in health and disease are comparatively sparse. The major objective of this research proposal is to address this issue and help to consolidate the field of neuroepigenetics by providing insight to the mechanisms by which epigenetic processes contribute to memory formation under physiological and pathological conditions. More specifically I will ask how the epigenetic code is translated into cellular changes that mediate memory formation in health and disease and how can epigenetic mechanisms contribute to the transmission of cognitive phenotypes even across generations. Our results will not only provide import insight to the mechanisms that underlie memory formation but will also lay the basis for the development of novel and improved therapies for age-related cognitive disorders.
Summary
The emerging field of neuroepigenetics investigates processes such as histone-acetylation in the context of neuronal plasticity, memory function and brain diseases. My group has significantly contributed to this novel research field. It is however fair to say that the role of “epigenetics” in memory function is still met with some skepticism in the neurosciences, which is in part due to the fact that many of the current studies have been describing phenomena and mechanistic data to explain how epigenetic processes control memory function in health and disease are comparatively sparse. The major objective of this research proposal is to address this issue and help to consolidate the field of neuroepigenetics by providing insight to the mechanisms by which epigenetic processes contribute to memory formation under physiological and pathological conditions. More specifically I will ask how the epigenetic code is translated into cellular changes that mediate memory formation in health and disease and how can epigenetic mechanisms contribute to the transmission of cognitive phenotypes even across generations. Our results will not only provide import insight to the mechanisms that underlie memory formation but will also lay the basis for the development of novel and improved therapies for age-related cognitive disorders.
Max ERC Funding
1 729 125 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym DynaSens
Project Understanding the neural mechanisms of multisensory perception based on computational principles
Researcher (PI) Christoph Kayser
Host Institution (HI) UNIVERSITAET BIELEFELD
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The brain’s multisensory faculty provides considerable benefits for perception, as the adaptive weighting of multiple inputs increases perceptual reliability and flexibility. However, failure of this process results in an impoverished percept, and links to perceptual deficits that occur along our life span and in disorders such as Autism. While the brain efficiently handles multiple sensory inputs, we still have a limited understanding of the underlying neural mechanisms. To advance our knowledge of how the brain processes its environment I propose a pioneering agenda that departs from previous descriptive work by linking the underlying brain mechanisms with specific multisensory computations and perception.
Precisely, I propose a programme that combines computational models of multisensory interactions with high-density neuroimaging and perceptual tasks. This interdisciplinary research builds on my pioneering multisensory work but will provide a qualitatively new and principled understanding of the neural processes that implement the well-known perceptual benefits of multisensory information.
The proposed programme advances our knowledge by addressing the following timely questions: What are the neural processes transforming multiple sensory inputs to a unified representation guiding behaviour? How does the brain control the dynamic weighting of multiple inputs and assigns these to either a single or multiple causes? Which perceptual and neural processes are affected in the multisensory deficits seen in autistic individuals or the elderly?
This agenda, by its innovative methods and deliverables, will offer a principled and comprehensive understanding of how the brain handles and merges multiple sensory inputs, and provides a framework for addressing continuing and pressing problems associated with multisensory processing deficits seen in cognitive disorders and during our life span.
Summary
The brain’s multisensory faculty provides considerable benefits for perception, as the adaptive weighting of multiple inputs increases perceptual reliability and flexibility. However, failure of this process results in an impoverished percept, and links to perceptual deficits that occur along our life span and in disorders such as Autism. While the brain efficiently handles multiple sensory inputs, we still have a limited understanding of the underlying neural mechanisms. To advance our knowledge of how the brain processes its environment I propose a pioneering agenda that departs from previous descriptive work by linking the underlying brain mechanisms with specific multisensory computations and perception.
Precisely, I propose a programme that combines computational models of multisensory interactions with high-density neuroimaging and perceptual tasks. This interdisciplinary research builds on my pioneering multisensory work but will provide a qualitatively new and principled understanding of the neural processes that implement the well-known perceptual benefits of multisensory information.
The proposed programme advances our knowledge by addressing the following timely questions: What are the neural processes transforming multiple sensory inputs to a unified representation guiding behaviour? How does the brain control the dynamic weighting of multiple inputs and assigns these to either a single or multiple causes? Which perceptual and neural processes are affected in the multisensory deficits seen in autistic individuals or the elderly?
This agenda, by its innovative methods and deliverables, will offer a principled and comprehensive understanding of how the brain handles and merges multiple sensory inputs, and provides a framework for addressing continuing and pressing problems associated with multisensory processing deficits seen in cognitive disorders and during our life span.
Max ERC Funding
1 909 441 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym EDeN
Project Ependymal cell Development: New insight into neurological diseases
Researcher (PI) Nathalie Anne Spassky
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Understanding how billions of neurons are born, migrate and integrate into functional circuits has proved useful in elucidating the pathomechanisms of many neurodevelopmental disorders. Multiciliated ependymal cells have attracted less interest and their development is still enigmatic. However, their strategic location at the interface between brain ventricles and parenchyma and their unique morphology and functions strongly suggest that defects in the generation of these cells may be associated with a variety of severe neurological disorders.
Multiciliated ependymal cells are epithelial cells that line all brain ventricles. The coordinated and oriented beating of their cilia is crucial for the flow of cerebrospinal fluid through the ventricles and the migration of new neurons. These cells also provide physical and trophic support that creates a permissive neurogenic environment in the adult.
We have shown that elongated bipolar radial glial cells transform into ependymal cells at late embryonic stages through mechanisms that remain largely to be explored. The overall objective of this grant application is to develop a new line of research to understand the cellular and molecular mechanisms involved in ependymal cell development. We will use a multidisciplinary approach involving mouse molecular genetics, biophysical approaches, ex-vivo culture systems and advanced live cell imaging to investigate: i) the mechanisms that direct the transformation of RGC into ependymal cells; ii) the mechanisms of centriole amplification in ependymal cell progenitors; iii) how developing ependymal cells contribute to ventricular morphogenesis and adult neurogenesis. This ambitious project will pave the way for the identification of new therapeutic targets for a variety of neurological disorders.
Summary
Understanding how billions of neurons are born, migrate and integrate into functional circuits has proved useful in elucidating the pathomechanisms of many neurodevelopmental disorders. Multiciliated ependymal cells have attracted less interest and their development is still enigmatic. However, their strategic location at the interface between brain ventricles and parenchyma and their unique morphology and functions strongly suggest that defects in the generation of these cells may be associated with a variety of severe neurological disorders.
Multiciliated ependymal cells are epithelial cells that line all brain ventricles. The coordinated and oriented beating of their cilia is crucial for the flow of cerebrospinal fluid through the ventricles and the migration of new neurons. These cells also provide physical and trophic support that creates a permissive neurogenic environment in the adult.
We have shown that elongated bipolar radial glial cells transform into ependymal cells at late embryonic stages through mechanisms that remain largely to be explored. The overall objective of this grant application is to develop a new line of research to understand the cellular and molecular mechanisms involved in ependymal cell development. We will use a multidisciplinary approach involving mouse molecular genetics, biophysical approaches, ex-vivo culture systems and advanced live cell imaging to investigate: i) the mechanisms that direct the transformation of RGC into ependymal cells; ii) the mechanisms of centriole amplification in ependymal cell progenitors; iii) how developing ependymal cells contribute to ventricular morphogenesis and adult neurogenesis. This ambitious project will pave the way for the identification of new therapeutic targets for a variety of neurological disorders.
Max ERC Funding
1 999 484 €
Duration
Start date: 2015-12-01, End date: 2020-11-30
Project acronym gluactive
Project Activation Mechanism of a Glutamate Receptor
Researcher (PI) Andrew John Robert Plested
Host Institution (HI) FORSCHUNGSVERBUND BERLIN EV
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Glutamate receptors are amongst the most important signalling molecules in the brain. Activation of receptors by the neurotransmitter glutamate is required for nervous system function, underlying cognition, learning, memory and sensation. Despite advances in the study of their structural biology and physiology, how glutamate receptor complexes are activated remains unclear. With this proposal, we aim to determine how receptor activation and desensitisation are driven by glutamate binding. Our central approach is to map the motions of glutamate receptors during synaptic-like activity, in order to grab the frames needed to produce the movie of receptor activation. We aim to detect motion within the receptor on the angstrom scale by trapping conformational states during activation with artificial metal ion binding sites and disulfide bonds. Trapped receptors will be examined using biochemical measures of subunit association, biophysical reports of receptor activity and by structural biology. The results we obtain will be useful to rationally interfere with excitatory synapses in the brain and may therefore help the development of therapies.
Summary
Glutamate receptors are amongst the most important signalling molecules in the brain. Activation of receptors by the neurotransmitter glutamate is required for nervous system function, underlying cognition, learning, memory and sensation. Despite advances in the study of their structural biology and physiology, how glutamate receptor complexes are activated remains unclear. With this proposal, we aim to determine how receptor activation and desensitisation are driven by glutamate binding. Our central approach is to map the motions of glutamate receptors during synaptic-like activity, in order to grab the frames needed to produce the movie of receptor activation. We aim to detect motion within the receptor on the angstrom scale by trapping conformational states during activation with artificial metal ion binding sites and disulfide bonds. Trapped receptors will be examined using biochemical measures of subunit association, biophysical reports of receptor activity and by structural biology. The results we obtain will be useful to rationally interfere with excitatory synapses in the brain and may therefore help the development of therapies.
Max ERC Funding
1 981 500 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym HUMO
Project What is everybody doing? Social prediction, categorization, and monitoring in the Prefrontal Cortex of the Macaque adopting a new human-monkey (H-M) interactive paradigm.
Researcher (PI) Aldo Genovesio
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Summary
Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Max ERC Funding
1 028 750 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym Myelination
Project Cell biology of myelin wrapping, plasticity and turnover
Researcher (PI) Mikael Jakob Simons
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The myelin sheath is a plasma membrane extension that is laid down in regular spaced segments along axons of the nervous system. In the central nervous system it is formed by oligodendrocytes that spirally wrap their plasma membrane around axons to generate a highly abundant, tightly packed stack of membranes with unique structural properties. Previously, myelin has been regarded as an inert and purely insulating membrane, but it now appears that myelin is metabolically active, providing metabolic support to the underlying axon and participating in information processing by modulating velocity and synchronicity of nerve impulses in neuronal networks. In addition, myelination is not limited to the period of early post-natal development, but continuous into adulthood where it appears to be regulated by neuronal stimuli. This paradigm shift should be fuelled by new knowledge about myelin biology. Here, we plan to fill this gap by addressing the molecular basis of myelin growth, plasticity and remodelling. We will determine the factors that determine whether and to what extent an axon will be myelinated or not, the forces that drive myelin around the axon, the structural basis of myelin plasticity and the mechanisms of myelin turnover in the adult. We will test the hypothesis that microglia actively participate in myelin turnover by taking up myelin fragments that pinch off from the myelin sheath. To realize these aims we plan to pursue an integrative and multidisciplinary approach by bringing together genetics, biochemistry, proteomics and imaging in various model systems. The innovation arises from the combination of high-resolution imaging with molecular approaches in different cell types to obtain a unifying mechanistic understanding of myelin formation, maintenance and degradation. If successful, the project would not only explain how myelin is generated during brain development, but also give insight into how myelin plasticity could fine-tune neuronal networks.
Summary
The myelin sheath is a plasma membrane extension that is laid down in regular spaced segments along axons of the nervous system. In the central nervous system it is formed by oligodendrocytes that spirally wrap their plasma membrane around axons to generate a highly abundant, tightly packed stack of membranes with unique structural properties. Previously, myelin has been regarded as an inert and purely insulating membrane, but it now appears that myelin is metabolically active, providing metabolic support to the underlying axon and participating in information processing by modulating velocity and synchronicity of nerve impulses in neuronal networks. In addition, myelination is not limited to the period of early post-natal development, but continuous into adulthood where it appears to be regulated by neuronal stimuli. This paradigm shift should be fuelled by new knowledge about myelin biology. Here, we plan to fill this gap by addressing the molecular basis of myelin growth, plasticity and remodelling. We will determine the factors that determine whether and to what extent an axon will be myelinated or not, the forces that drive myelin around the axon, the structural basis of myelin plasticity and the mechanisms of myelin turnover in the adult. We will test the hypothesis that microglia actively participate in myelin turnover by taking up myelin fragments that pinch off from the myelin sheath. To realize these aims we plan to pursue an integrative and multidisciplinary approach by bringing together genetics, biochemistry, proteomics and imaging in various model systems. The innovation arises from the combination of high-resolution imaging with molecular approaches in different cell types to obtain a unifying mechanistic understanding of myelin formation, maintenance and degradation. If successful, the project would not only explain how myelin is generated during brain development, but also give insight into how myelin plasticity could fine-tune neuronal networks.
Max ERC Funding
1 872 500 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
