Project acronym AstroFunc
Project Molecular Studies of Astrocyte Function in Health and Disease
Researcher (PI) Matthew Guy Holt
Host Institution (HI) VIB VZW
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary Brain consists of two basic cell types – neurons and glia. However, the study of glia in brain function has traditionally been neglected in favor of their more “illustrious” counter-parts – neurons that are classed as the computational units of the brain. Glia have usually been classed as “brain glue” - a supportive matrix on which neurons grow and function. However, recent evidence suggests that glia are more than passive “glue” and actually modulate neuronal function. This has lead to the proposal of a “tripartite synapse”, which recognizes pre- and postsynaptic neuronal elements and glia as a unit.
However, what is still lacking is rudimentary information on how these cells actually function in situ. Here we propose taking a “bottom-up” approach, by identifying the molecules (and interactions) that control glial function in situ. This is complicated by the fact that glia show profound changes when placed into culture. To circumvent this, we will use recently developed cell sorting techniques, to rapidly isolate genetically marked glial cells from brain – which can then be analyzed using advanced biochemical and physiological techniques. The long-term aim is to identify proteins that can be “tagged” using transgenic technologies to allow protein function to be studied in real-time in vivo, using sophisticated imaging techniques. Given the number of proteins that may be identified we envisage developing new methods of generating transgenic animals that provide an attractive alternative to current “state-of-the art” technology.
The importance of studying glial function is given by the fact that every major brain pathology shows reactive gliosis. In the time it takes to read this abstract, 5 people in the EU will have suffered a stroke – not to mention those who suffer other forms of neurotrauma. Thus, understanding glial function is not only critical to understanding normal brain function, but also for relieving the burden of severe neurological injury and disease
Summary
Brain consists of two basic cell types – neurons and glia. However, the study of glia in brain function has traditionally been neglected in favor of their more “illustrious” counter-parts – neurons that are classed as the computational units of the brain. Glia have usually been classed as “brain glue” - a supportive matrix on which neurons grow and function. However, recent evidence suggests that glia are more than passive “glue” and actually modulate neuronal function. This has lead to the proposal of a “tripartite synapse”, which recognizes pre- and postsynaptic neuronal elements and glia as a unit.
However, what is still lacking is rudimentary information on how these cells actually function in situ. Here we propose taking a “bottom-up” approach, by identifying the molecules (and interactions) that control glial function in situ. This is complicated by the fact that glia show profound changes when placed into culture. To circumvent this, we will use recently developed cell sorting techniques, to rapidly isolate genetically marked glial cells from brain – which can then be analyzed using advanced biochemical and physiological techniques. The long-term aim is to identify proteins that can be “tagged” using transgenic technologies to allow protein function to be studied in real-time in vivo, using sophisticated imaging techniques. Given the number of proteins that may be identified we envisage developing new methods of generating transgenic animals that provide an attractive alternative to current “state-of-the art” technology.
The importance of studying glial function is given by the fact that every major brain pathology shows reactive gliosis. In the time it takes to read this abstract, 5 people in the EU will have suffered a stroke – not to mention those who suffer other forms of neurotrauma. Thus, understanding glial function is not only critical to understanding normal brain function, but also for relieving the burden of severe neurological injury and disease
Max ERC Funding
1 490 168 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BRAINSHAPE
Project Objects in sight: the neural basis of visuomotor transformations for actions towards objects
Researcher (PI) Peter Anna J Janssen
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.
Summary
Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.
Max ERC Funding
1 499 200 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
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
Project acronym GENDEVOCORTEX
Project Genetic links between development and evolution of the human cerebral cortex
Researcher (PI) Pierre Vanderhaeghen
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary "The mechanisms underlying the evolution of the human brain constitute one of the most fascinating unresolved questions of biology. The cerebral cortex has evolved rapidly in size and complexity in the hominid lineage, which is likely linked to quantitative and qualitative divergence in patterns of cortical development.
On the other hand, comparative genomics has revealed recently the existence of a number of ""hominid-specific"" genes, which constitute attractive candidates to underlie critical aspects of human brain evolution, but their function remains essentially unexplored, mostly because of the lack of appropriate experimental systems.
Here we propose to test a simple and radical hypothesis: that key species-specific features of the development of the human cerebral cortex, in particular the generation and differentiation of pyramidal neurons, are linked functionally to the emergence of hominid-specific (HS) genes controlling corticogenesis.
To achieve this high risk / high gain goal, we will first determine which HS genes are expressed in the human developing cortex in vivo, using a combination of genome-wide and in situ gene detection analyses, in order to select those most likely to impact corticogenesis.
The function of candidate HS genes will be determined using innovative models of human corticogenesis based on pluripotent stem cells, developed recently in our laboratory, as well as ex vivo cultures of human fetal cortex. In addition, the developmental and evolutionary impact of HS genes will be examined in a non-hominid context, the mouse embryonic cortex.
By identifying the function of hominid-specific genes in cortical developpment, we will uncover specific genetic mechanisms linking functionally the development and evolution of the human brain, with broad implications in neurobiology, developmental and evolutionary biology."
Summary
"The mechanisms underlying the evolution of the human brain constitute one of the most fascinating unresolved questions of biology. The cerebral cortex has evolved rapidly in size and complexity in the hominid lineage, which is likely linked to quantitative and qualitative divergence in patterns of cortical development.
On the other hand, comparative genomics has revealed recently the existence of a number of ""hominid-specific"" genes, which constitute attractive candidates to underlie critical aspects of human brain evolution, but their function remains essentially unexplored, mostly because of the lack of appropriate experimental systems.
Here we propose to test a simple and radical hypothesis: that key species-specific features of the development of the human cerebral cortex, in particular the generation and differentiation of pyramidal neurons, are linked functionally to the emergence of hominid-specific (HS) genes controlling corticogenesis.
To achieve this high risk / high gain goal, we will first determine which HS genes are expressed in the human developing cortex in vivo, using a combination of genome-wide and in situ gene detection analyses, in order to select those most likely to impact corticogenesis.
The function of candidate HS genes will be determined using innovative models of human corticogenesis based on pluripotent stem cells, developed recently in our laboratory, as well as ex vivo cultures of human fetal cortex. In addition, the developmental and evolutionary impact of HS genes will be examined in a non-hominid context, the mouse embryonic cortex.
By identifying the function of hominid-specific genes in cortical developpment, we will uncover specific genetic mechanisms linking functionally the development and evolution of the human brain, with broad implications in neurobiology, developmental and evolutionary biology."
Max ERC Funding
2 473 937 €
Duration
Start date: 2014-08-01, End date: 2019-07-31
Project acronym MIRNA_AD
Project Role of microRNA dysregulation in Alzheimers Disease
Researcher (PI) Bart Geert Alfons Paul De Strooper
Host Institution (HI) VIB VZW
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Alzheimer's Disease (AD) is a major health problem in aging societies. Remarkable progress in the study of the rare genetic forms of the disease has lead to the identification of several key players like APP and the secretases, but the molecular basis of sporadic AD remains largely unresolved. The convergence of several factors (multicausality) has to be considered. miRNAs are crucially involved in normal brain functioning and integrity. Evidence obtained from analyzing a limited number of brains indicates that miRNA expression is affected in sporadic AD. We propose the hypothesis that such changes can affect normal functioning of neurons increasing their susceptibility to AD. We will document in 3 brain regions in >100 sporadic AD patients and in >100 controls alterations in miRNA expression and explore whether similar alterations can be detected in cerebrospinal fluid. This part of the study will firmly establish which miRNAs are altered in AD. We will then investigate the functional relevance of those miRNAs by gain and loss of function experiments in brains of zebra fish and mice. We will determine the target genes of the miRNA with genetic and proteomic approaches, and establish the functional networks controlled by those miRNA. We anticipate that this will lead to complete novel insights in the role of miRNAs in AD and in maintenance of brain integrity. Our work is likely to have diagnostic relevance for AD and will identify novel drug targets for the disease.
Summary
Alzheimer's Disease (AD) is a major health problem in aging societies. Remarkable progress in the study of the rare genetic forms of the disease has lead to the identification of several key players like APP and the secretases, but the molecular basis of sporadic AD remains largely unresolved. The convergence of several factors (multicausality) has to be considered. miRNAs are crucially involved in normal brain functioning and integrity. Evidence obtained from analyzing a limited number of brains indicates that miRNA expression is affected in sporadic AD. We propose the hypothesis that such changes can affect normal functioning of neurons increasing their susceptibility to AD. We will document in 3 brain regions in >100 sporadic AD patients and in >100 controls alterations in miRNA expression and explore whether similar alterations can be detected in cerebrospinal fluid. This part of the study will firmly establish which miRNAs are altered in AD. We will then investigate the functional relevance of those miRNAs by gain and loss of function experiments in brains of zebra fish and mice. We will determine the target genes of the miRNA with genetic and proteomic approaches, and establish the functional networks controlled by those miRNA. We anticipate that this will lead to complete novel insights in the role of miRNAs in AD and in maintenance of brain integrity. Our work is likely to have diagnostic relevance for AD and will identify novel drug targets for the disease.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym ModifALS
Project From zebrafish to man
Modifying amyotrophic lateral sclerosis (ALS): translation of biology into therapy
Researcher (PI) Wim Robberecht
Host Institution (HI) VIB VZW
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neurons. As for other neurodegenerative disorders, translation of newly acquired biological insights into therapies has been difficult. In the current project we intend to contribute to the development of therapeutic approaches for ALS. We want to generate novel models, identify new therapeutic targets for intervention, and translate these into validated options for drug development in ALS. This will be done by establishing a continuous line of research from the (unbiased) screening for targets in a small animal model (zebrafish), to the exploration of their therapeutic potential, and the validation in patients. In addition, by exploring the significance of some of the findings for other neurodegenerative disorders, we hope to demonstrate this approach to be valid for the field of neurodegenerative disorders in general. This research will be performed bases on 6 work packages (WP): 1.screening of a zebrafish model for ALS to identify therapeutic targets; 2. validation of these targets in larger vertebrate ALS models; 3. investigation of the mechanism of action of these targets in order to establish approaches to interfere with them; 4. validation of these targets in human ALS; 5. generation of preclinical data on these targets; 6. exploration of the possible role of these targets in other neurodegenerative diseases.
Results from WP1 will be used for further research in WP2, results from WP2 in WP3, etc. We have gathered a large set of data in preparatory work in zebrafish, enabling us to start all WPs from the beginning of the project on.
This project involves collaborations with several other groups, national and international, which all have been established. Furthermore, all transgenic mice needed to initiate all these WPs have been generated and available to us.
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neurons. As for other neurodegenerative disorders, translation of newly acquired biological insights into therapies has been difficult. In the current project we intend to contribute to the development of therapeutic approaches for ALS. We want to generate novel models, identify new therapeutic targets for intervention, and translate these into validated options for drug development in ALS. This will be done by establishing a continuous line of research from the (unbiased) screening for targets in a small animal model (zebrafish), to the exploration of their therapeutic potential, and the validation in patients. In addition, by exploring the significance of some of the findings for other neurodegenerative disorders, we hope to demonstrate this approach to be valid for the field of neurodegenerative disorders in general. This research will be performed bases on 6 work packages (WP): 1.screening of a zebrafish model for ALS to identify therapeutic targets; 2. validation of these targets in larger vertebrate ALS models; 3. investigation of the mechanism of action of these targets in order to establish approaches to interfere with them; 4. validation of these targets in human ALS; 5. generation of preclinical data on these targets; 6. exploration of the possible role of these targets in other neurodegenerative diseases.
Results from WP1 will be used for further research in WP2, results from WP2 in WP3, etc. We have gathered a large set of data in preparatory work in zebrafish, enabling us to start all WPs from the beginning of the project on.
This project involves collaborations with several other groups, national and international, which all have been established. Furthermore, all transgenic mice needed to initiate all these WPs have been generated and available to us.
Max ERC Funding
2 467 990 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym PEPTIDELEARNING
Project The Role of Neuropeptides in Learning and Memory
Researcher (PI) Liliane Schoofs
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary Humanity has always been intrigued by the nearly mythical properties of the brain. With its billions of neurons and innumerable connections, the brain is of such complex nature, that trying to understand it may seem a vain project. Yet, by using the ‘mini-brain’ of the model organism Caenorhabditis elegans, which shares many components with the human brain but counts only 302 neurons, thorough research can penetrate into this complexity. We here pursue to deliver a much-needed understanding of how learning and memory processes are regulated by neuropeptide signaling in the brain. Neuropeptides are small regulatory proteins that are implicated in a variety of processes. Growing evidence exists for their involvement in learning and memory, but how they exert these effects is largely unexplored. In C. elegans we recently disentangled a conserved vasopressin/ocytocin-related system that –as in humans– mediates associative learning. As such, we can deliver the experience, model and logical approach to provide detailed insights in neuropeptidergic control of learning and memory. We will first identify the endogenous ligand of all orphan C. elegans neuropeptide GPCRs, as this will provide the essential basis to build this project on. Mutants of neuropeptide-receptor pairs will then be tested for their ability to learn or maintain associative short- or long-term memory. We will also define in which cells and circuits relevant neuropeptides and receptors are needed for these functions, in order to generate models of neuropeptidergic control of learning and memory. We envisage the use of novel tools and cutting-edge experimental setups to take this research beyond its current horizon. Via single cell RNA sequencing, optogenetic analyses and in vivo calcium imaging, we will develop a workflow to build integrative models of associative learning and memory processes mediated by neuropeptides, which will serve as a scaffold for the study of these processes in more complex brains.
Summary
Humanity has always been intrigued by the nearly mythical properties of the brain. With its billions of neurons and innumerable connections, the brain is of such complex nature, that trying to understand it may seem a vain project. Yet, by using the ‘mini-brain’ of the model organism Caenorhabditis elegans, which shares many components with the human brain but counts only 302 neurons, thorough research can penetrate into this complexity. We here pursue to deliver a much-needed understanding of how learning and memory processes are regulated by neuropeptide signaling in the brain. Neuropeptides are small regulatory proteins that are implicated in a variety of processes. Growing evidence exists for their involvement in learning and memory, but how they exert these effects is largely unexplored. In C. elegans we recently disentangled a conserved vasopressin/ocytocin-related system that –as in humans– mediates associative learning. As such, we can deliver the experience, model and logical approach to provide detailed insights in neuropeptidergic control of learning and memory. We will first identify the endogenous ligand of all orphan C. elegans neuropeptide GPCRs, as this will provide the essential basis to build this project on. Mutants of neuropeptide-receptor pairs will then be tested for their ability to learn or maintain associative short- or long-term memory. We will also define in which cells and circuits relevant neuropeptides and receptors are needed for these functions, in order to generate models of neuropeptidergic control of learning and memory. We envisage the use of novel tools and cutting-edge experimental setups to take this research beyond its current horizon. Via single cell RNA sequencing, optogenetic analyses and in vivo calcium imaging, we will develop a workflow to build integrative models of associative learning and memory processes mediated by neuropeptides, which will serve as a scaffold for the study of these processes in more complex brains.
Max ERC Funding
2 463 028 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym PROBING-PAIN
Project Multimodal functional neuroimaging techniques to probe the representation of pain in the human brain
Researcher (PI) Andre Philippe J Mouraux
Host Institution (HI) UNIVERSITE CATHOLIQUE DE LOUVAIN
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary "Pain may be defined as a primarily aversive perception that is vital for survival, as it incites the individual to respond to stimuli constituting a real or potential menace. However, pain is also a major healthcare issue, undermining the health and welfare of millions of individuals and imposing a severe financial burden to our societies. How does the brain process noxious stimuli, and how does this lead to the perception of pain? In humans, using functional neuroimaging techniques such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI), a great number of studies have shown that noxious stimuli elicit activity within a widespread network of cortical regions, including the primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex. However, recent studies have suggested that these responses are largely unspecific for pain and, instead, reflect attentional mechanisms that can be triggered by the occurrence of any salient sensory event, regardless of whether it elicits pain.
Therefore, novel approaches are needed to progress in understanding the neural representation of pain in humans. This constitutes the main objective of this project in which we will develop a series of original experimental approaches to (1) explore how transient and sustained pain are respectively represented in the human brain, (2) characterize directly the functional connectivity, interdependency and hierarchical organization of the different brain regions involved in the perception of pain and (3) characterize the plastic changes in cortical excitability and functional connectivity induced by sustained experimental pain as well as chronic pathological pain. Each of these approaches has the potential to open a new line of research for basic and clinical pain neuroscience, with important development perspectives, such as the identification of novel human biomarkers for analgesic drug development and improved patient stratification."
Summary
"Pain may be defined as a primarily aversive perception that is vital for survival, as it incites the individual to respond to stimuli constituting a real or potential menace. However, pain is also a major healthcare issue, undermining the health and welfare of millions of individuals and imposing a severe financial burden to our societies. How does the brain process noxious stimuli, and how does this lead to the perception of pain? In humans, using functional neuroimaging techniques such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI), a great number of studies have shown that noxious stimuli elicit activity within a widespread network of cortical regions, including the primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex. However, recent studies have suggested that these responses are largely unspecific for pain and, instead, reflect attentional mechanisms that can be triggered by the occurrence of any salient sensory event, regardless of whether it elicits pain.
Therefore, novel approaches are needed to progress in understanding the neural representation of pain in humans. This constitutes the main objective of this project in which we will develop a series of original experimental approaches to (1) explore how transient and sustained pain are respectively represented in the human brain, (2) characterize directly the functional connectivity, interdependency and hierarchical organization of the different brain regions involved in the perception of pain and (3) characterize the plastic changes in cortical excitability and functional connectivity induced by sustained experimental pain as well as chronic pathological pain. Each of these approaches has the potential to open a new line of research for basic and clinical pain neuroscience, with important development perspectives, such as the identification of novel human biomarkers for analgesic drug development and improved patient stratification."
Max ERC Funding
1 484 334 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym RobustSynapses
Project Maintaining synaptic function for a healthy brain: Membrane trafficking and autophagy in neurodegeneration
Researcher (PI) Patrik Verstreken
Host Institution (HI) VIB VZW
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.
Summary
Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.
Max ERC Funding
1 999 025 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym SleepSynapses
Project The role of sleep in synaptic plasticity
Researcher (PI) Sha LIU
Host Institution (HI) VIB VZW
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary Although we spend a third of our lives sleeping, the function of sleep remains mysterious. Studies considering neural networks, brain regions and behavior suggest the intriguing hypothesis that sleep is important for synaptic plasticity. However, as prior studies have conducted analyses using broad brain regions or circuit networks, the precise role of sleep in synaptic plasticity remains intensely debated. Progress in this area is hindered by the lack of a genetically-tractable system of sleep-dependent synaptic plasticity. To solve this, I developed a unique fruit fly model. It is the first model of its kind in which the cellular players comprising the synapses can be genetically labelled and manipulated. I will use this model to address a long-running controversy in the field--which form(s) of synaptic plasticity is promoted by sleep--by directly monitoring the effects of sleep on precisely identified synapses at electrophysiological and ultrastructural levels. Then, I will investigate the mechanisms underlying this process by analyzing the effects of sleep on every cellular component (pre and postsynaptic neurons and perisynaptic astrocytes) in this model at molecular and cellular levels. Emerging data suggest that astrocytes play a key role in synaptic plasticity and have further implicated these cells in regulating sleep. However, it has been difficult to directly examine the role of astrocytes in sleep-dependent synaptic plasticity, since no methodology currently exists for reproducibly manipulating local astrocytes enveloping the synapse of interest. For this, I will implement a unique tool, named G-CLAMP, and use it to assess potential glial mechanisms underlying sleep-dependent plasticity. Considered as a whole, my project will produce unique and comprehensive understanding of the role of sleep in synaptic plasticity, an essential question if we aim to understand sleep, and move us towards explaining the evolutionarily origins of this mysterious behavior.
Summary
Although we spend a third of our lives sleeping, the function of sleep remains mysterious. Studies considering neural networks, brain regions and behavior suggest the intriguing hypothesis that sleep is important for synaptic plasticity. However, as prior studies have conducted analyses using broad brain regions or circuit networks, the precise role of sleep in synaptic plasticity remains intensely debated. Progress in this area is hindered by the lack of a genetically-tractable system of sleep-dependent synaptic plasticity. To solve this, I developed a unique fruit fly model. It is the first model of its kind in which the cellular players comprising the synapses can be genetically labelled and manipulated. I will use this model to address a long-running controversy in the field--which form(s) of synaptic plasticity is promoted by sleep--by directly monitoring the effects of sleep on precisely identified synapses at electrophysiological and ultrastructural levels. Then, I will investigate the mechanisms underlying this process by analyzing the effects of sleep on every cellular component (pre and postsynaptic neurons and perisynaptic astrocytes) in this model at molecular and cellular levels. Emerging data suggest that astrocytes play a key role in synaptic plasticity and have further implicated these cells in regulating sleep. However, it has been difficult to directly examine the role of astrocytes in sleep-dependent synaptic plasticity, since no methodology currently exists for reproducibly manipulating local astrocytes enveloping the synapse of interest. For this, I will implement a unique tool, named G-CLAMP, and use it to assess potential glial mechanisms underlying sleep-dependent plasticity. Considered as a whole, my project will produce unique and comprehensive understanding of the role of sleep in synaptic plasticity, an essential question if we aim to understand sleep, and move us towards explaining the evolutionarily origins of this mysterious behavior.
Max ERC Funding
1 706 250 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
