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 BRAINVISIONREHAB
Project ‘Seeing’ with the ears, hands and bionic eyes: from theories about brain organization to visual rehabilitation
Researcher (PI) Amir Amedi
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Summary
My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Max ERC Funding
1 499 900 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
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
Project acronym C.o.C.O.
Project Circuits of con-specific observation
Researcher (PI) Marta De Aragao Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Summary
A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.
Max ERC Funding
1 412 376 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
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: 2021-03-31
Project acronym CANALOHMICS
Project Biophysical networks underlying the robustness of neuronal excitability
Researcher (PI) Jean-Marc Goaillard
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Summary
The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information.
So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined.
In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.
Max ERC Funding
1 972 797 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym CARV
Project Chemical Approaches to Restoring Vision
Researcher (PI) Dirk Trauner
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Blindness affects millions of people worldwide and has devastating consequences for those affected. It is often caused by a loss of photoreceptors in the retina, whose residual cellular network remains largely unaffected. Various strategies have been chosen to restore vision, such as electrical stimulation with retinal implants. More recently, natural photoreceptor proteins and stem cells have been explored. We propose a radically different ¿photopharmacological¿ approach toward vision restoration that is based on synthetic photoswitches. These are combined in various ways with natural receptor proteins to create hybrid photoreceptors, which can then sensitize neurons toward light. In a way we are ¿teaching old receptors new tricks¿ and let them carry out functions that they have not evolved for in Nature. Our hybrid photoreceptors and photochromic drugs work well in experimental animals and have already been shown to influence their visual behavior. To make these molecules work in humans, we need to improve their photophysical properties and investigate their delivery, stability and pharmacology. This requires an extensive program in synthetic chemistry, which should be accompanied by effective and immediate neurobiological evaluation. Our very general approach to optically controlling neural activity can be applied to other functions and malfunctions of the nervous system, such as pain or epilepsy, but its greatest medical potential currently lies in the restoration of vision.
Summary
Blindness affects millions of people worldwide and has devastating consequences for those affected. It is often caused by a loss of photoreceptors in the retina, whose residual cellular network remains largely unaffected. Various strategies have been chosen to restore vision, such as electrical stimulation with retinal implants. More recently, natural photoreceptor proteins and stem cells have been explored. We propose a radically different ¿photopharmacological¿ approach toward vision restoration that is based on synthetic photoswitches. These are combined in various ways with natural receptor proteins to create hybrid photoreceptors, which can then sensitize neurons toward light. In a way we are ¿teaching old receptors new tricks¿ and let them carry out functions that they have not evolved for in Nature. Our hybrid photoreceptors and photochromic drugs work well in experimental animals and have already been shown to influence their visual behavior. To make these molecules work in humans, we need to improve their photophysical properties and investigate their delivery, stability and pharmacology. This requires an extensive program in synthetic chemistry, which should be accompanied by effective and immediate neurobiological evaluation. Our very general approach to optically controlling neural activity can be applied to other functions and malfunctions of the nervous system, such as pain or epilepsy, but its greatest medical potential currently lies in the restoration of vision.
Max ERC Funding
2 484 613 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym CCC
Project Cracking the Cerebellar Code
Researcher (PI) Christiaan Innocentius De Zeeuw
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Summary
Spike trains transfer information to and from neurons. Most studies so far assume that the average firing rate or “rate coding” is the predominant way of information coding. However, spikes occur at millisecond precision, and their actual timing or “temporal coding” can in principle strongly increase the information content of spike trains. The two coding mechanisms are not mutually exclusive. Neurons may switch between rate and temporal coding, or use a combination of both coding mechanisms at the same time, which would increase the information content of spike trains even further. Here, we propose to investigate the hypothesis that temporal coding plays, next to rate coding, important and specific roles in cerebellar processing during learning. The cerebellum is ideal to study this timely topic, because it has a clear anatomy with well-organized modules and matrices, a well-described physiology of different types of neurons with distinguishable spiking activity, and a central role in various forms of tractable motor learning. Moreover, uniquely in the brain, the main types of neurons in the cerebellar system can be genetically manipulated in a cell-specific fashion, which will allow us to investigate the behavioural importance of both coding mechanisms following cell-specific interference and/or during cell-specific visual imaging. Thus, for this proposal we will create conditional mouse mutants that will be subjected to learning paradigms in which we can disentangle the contributions of rate coding and temporal coding using electrophysiological and optogenetic recordings and stimulation. Together, our experiments should elucidate how neurons in the brain communicate during natural learning behaviour and how one may be able to intervene in this process to affect or improve procedural learning skills.
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym CEIDNFSTTAIS
Project Controlling excitability in developing neurons: from synapses to the axon initial segment
Researcher (PI) Juan Burrone
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.
Summary
A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym CELLPHASE_AD
Project Genetics to understand cellular components of Alzheimer Disease pathogenesis
Researcher (PI) Bart Geert Alfons Paul DE STROOPER
Host Institution (HI) VIB VZW
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process.
Human stem cells (iPS) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field. We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau- pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated. In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 selected AD associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis.
Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.
Summary
Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process.
Human stem cells (iPS) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field. We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau- pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated. In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 selected AD associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis.
Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.
Max ERC Funding
2 374 998 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
