Project acronym 5HT-OPTOGENETICS
Project Optogenetic Analysis of Serotonin Function in the Mammalian Brain
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Summary
Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Max ERC Funding
2 318 636 €
Duration
Start date: 2010-07-01, End date: 2015-12-31
Project acronym 5HTCircuits
Project Modulation of cortical circuits and predictive neural coding by serotonin
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Summary
Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Max ERC Funding
2 486 074 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym ABACUS
Project Ab-initio adiabatic-connection curves for density-functional analysis and construction
Researcher (PI) Trygve Ulf Helgaker
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Advanced Grant (AdG), PE4, ERC-2010-AdG_20100224
Summary Quantum chemistry provides two approaches to molecular electronic-structure calculations: the systematically refinable but expensive many-body wave-function methods and the inexpensive but not systematically refinable Kohn Sham method of density-functional theory (DFT). The accuracy of Kohn Sham calculations is determined by the quality of the exchange correlation functional, from which the effects of exchange and correlation among the electrons are extracted using the density rather than the wave function. However, the exact exchange correlation functional is unknown—instead, many approximate forms have been developed, by fitting to experimental data or by satisfying exact relations. Here, a new approach to density-functional analysis and construction is proposed: the Lieb variation principle, usually regarded as conceptually important but impracticable. By invoking the Lieb principle, it becomes possible to approach the development of approximate functionals in a novel manner, being directly guided by the behaviour of exact functional, accurately calculated for a wide variety of chemical systems. In particular, this principle will be used to calculate ab-initio adiabatic connection curves, studying the exchange correlation functional for a fixed density as the electronic interactions are turned on from zero to one. Pilot calculations have indicated the feasibility of this approach in simple cases—here, a comprehensive set of adiabatic-connection curves will be generated and utilized for calibration, construction, and analysis of density functionals, the objective being to produce improved functionals for Kohn Sham calculations by modelling or fitting such curves. The ABACUS approach will be particularly important in cases where little experimental information is available—for example, for understanding and modelling the behaviour of the exchange correlation functional in electromagnetic fields.
Summary
Quantum chemistry provides two approaches to molecular electronic-structure calculations: the systematically refinable but expensive many-body wave-function methods and the inexpensive but not systematically refinable Kohn Sham method of density-functional theory (DFT). The accuracy of Kohn Sham calculations is determined by the quality of the exchange correlation functional, from which the effects of exchange and correlation among the electrons are extracted using the density rather than the wave function. However, the exact exchange correlation functional is unknown—instead, many approximate forms have been developed, by fitting to experimental data or by satisfying exact relations. Here, a new approach to density-functional analysis and construction is proposed: the Lieb variation principle, usually regarded as conceptually important but impracticable. By invoking the Lieb principle, it becomes possible to approach the development of approximate functionals in a novel manner, being directly guided by the behaviour of exact functional, accurately calculated for a wide variety of chemical systems. In particular, this principle will be used to calculate ab-initio adiabatic connection curves, studying the exchange correlation functional for a fixed density as the electronic interactions are turned on from zero to one. Pilot calculations have indicated the feasibility of this approach in simple cases—here, a comprehensive set of adiabatic-connection curves will be generated and utilized for calibration, construction, and analysis of density functionals, the objective being to produce improved functionals for Kohn Sham calculations by modelling or fitting such curves. The ABACUS approach will be particularly important in cases where little experimental information is available—for example, for understanding and modelling the behaviour of the exchange correlation functional in electromagnetic fields.
Max ERC Funding
2 017 932 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
Project acronym CIRCUIT
Project Neural circuits for space representation in the mammalian cortex
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Summary
Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Max ERC Funding
2 499 112 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym DAMONA
Project Mutation and Recombination in the Cattle Germline: Genomic Analysis and Impact on Fertility
Researcher (PI) Michel Alphonse Julien Georges
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary "Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination.
It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation.
Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to:
(i) quantify and characterize inter-individual variation in male and female mutation and recombination rates,
(ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes,
(iii) test the effect of loss-of-function variants on >50 traits including fertility, and
(iv) study the effect of variation in recombination on fertility."
Summary
"Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination.
It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation.
Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to:
(i) quantify and characterize inter-individual variation in male and female mutation and recombination rates,
(ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes,
(iii) test the effect of loss-of-function variants on >50 traits including fertility, and
(iv) study the effect of variation in recombination on fertility."
Max ERC Funding
2 258 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym DOUBLE-UP
Project The importance of gene and genome duplications for natural and artificial organism populations
Researcher (PI) Yves Eddy Philomena Van De Peer
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS2, ERC-2012-ADG_20120314
Summary The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.
Summary
The long-term establishment of ancient organisms that have undergone whole genome duplications has been exceedingly rare. On the other hand, tens of thousands of now-living species are polyploid and contain multiple copies of their genome. The paucity of ancient genome duplications and the existence of so many species that are currently polyploid provide an interesting and fascinating enigma. A question that remains is whether these older genome duplications have survived by coincidence or because they did occur at very specific times, for instance during major ecological upheavals and periods of extinction. It has indeed been proposed that chromosome doubling conveys greater stress tolerance by fostering slower development, delayed reproduction and longer life span. Furthermore, polyploids have also been considered to have greater ability to colonize new or disturbed habitats. If polyploidy allowed many plant lineages to survive and adapt during global changes, as suggested, we might wonder whether polyploidy will confer a similar advantage in the current period of global warming and general ecological pressure caused by the human race. Given predictions that species extinction is now occurring at as high rates as during previous mass extinctions, will the presumed extra adaptability of polyploid plants mean they will become the dominant species? In the current proposal, we hope to address these questions at different levels through 1) the analysis of whole plant genome sequence data and 2) the in silico modelling of artificial gene regulatory networks to mimic the genomic consequences of genome doubling and how this may affect network structure and dosage balance. Furthermore, we aim at using simulated robotic models running on artificial gene regulatory networks in complex environments to evaluate how both natural and artificial organism populations can potentially benefit from gene and genome duplications for adaptation, survival, and evolution in general.
Max ERC Funding
2 217 525 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym ECMETABOLISM
Project Targeting endothelial metabolism: a novel anti-angiogenic therapy
Researcher (PI) Peter Frans Martha Carmeliet
Host Institution (HI) VIB
Call Details Advanced Grant (AdG), LS2, ERC-2010-AdG_20100317
Summary Current anti-angiogenesis based anti-tumor therapy relies on starving tumors by blocking their vascular supply via inhibition of growth factors. However, limitations such as resistance and toxicity, mandate conceptually distinct approaches. We will explore an entirely novel and long-overlooked strategy to discover additional anti-angiogenic candidates, based on the following innovative concept: ¿rather than STARVING TUMORS BY BLOCKING THEIR VASCULAR SUPPLY, we intend TO STARVE BLOOD VESSELS BY BLOCKING THEIR METABOLIC ENERGY SUPPLY¿, so that new vessels cannot form and nourish the growing tumor. This project is a completely new research avenue in our group, but we expect that it will offer refreshing long-term research and translational opportunities for the field.
Because so little is known on endothelial cell (EC) metabolism, we will (i) via a multi-disciplinary systems-biology approach of transcriptomics, proteomics, computational network modeling, metabolomics and flux-omics, draw an endothelio-metabolic map in angiogenesis. This will allow us to identify metabolic regulators of angiogenesis, which will be further validated and characterized in (ii) loss and gain-of-function studies in various angiogenesis models in vitro and (iii) in vivo in zebrafish (knockdown; zinc finger nuclease mediated knockout), providing prescreen data to select the most promising candidates. (iv) EC-specific down-regulation (miR RNAi) or knockout studies of selected candidates in mice will confirm their relevance for angiogenic phenotypes in a preclinical model; and ultimately (v) a translational study evaluating EC metabolism-targeted anti-angiogenic strategies (pharmacological inhibitors, antibodies, small molecular compounds) will be performed in tumor models in the mouse.
Summary
Current anti-angiogenesis based anti-tumor therapy relies on starving tumors by blocking their vascular supply via inhibition of growth factors. However, limitations such as resistance and toxicity, mandate conceptually distinct approaches. We will explore an entirely novel and long-overlooked strategy to discover additional anti-angiogenic candidates, based on the following innovative concept: ¿rather than STARVING TUMORS BY BLOCKING THEIR VASCULAR SUPPLY, we intend TO STARVE BLOOD VESSELS BY BLOCKING THEIR METABOLIC ENERGY SUPPLY¿, so that new vessels cannot form and nourish the growing tumor. This project is a completely new research avenue in our group, but we expect that it will offer refreshing long-term research and translational opportunities for the field.
Because so little is known on endothelial cell (EC) metabolism, we will (i) via a multi-disciplinary systems-biology approach of transcriptomics, proteomics, computational network modeling, metabolomics and flux-omics, draw an endothelio-metabolic map in angiogenesis. This will allow us to identify metabolic regulators of angiogenesis, which will be further validated and characterized in (ii) loss and gain-of-function studies in various angiogenesis models in vitro and (iii) in vivo in zebrafish (knockdown; zinc finger nuclease mediated knockout), providing prescreen data to select the most promising candidates. (iv) EC-specific down-regulation (miR RNAi) or knockout studies of selected candidates in mice will confirm their relevance for angiogenic phenotypes in a preclinical model; and ultimately (v) a translational study evaluating EC metabolism-targeted anti-angiogenic strategies (pharmacological inhibitors, antibodies, small molecular compounds) will be performed in tumor models in the mouse.
Max ERC Funding
2 365 224 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym ENSEMBLE
Project Neural mechanisms for memory retrieval
Researcher (PI) May-Britt Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Summary
Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Max ERC Funding
2 499 074 €
Duration
Start date: 2011-11-01, End date: 2017-10-31
Project acronym FLUOROCODE
Project FLUOROCODE: a super-resolution optical map of DNA
Researcher (PI) Johan M. V. Hofkens
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Advanced Grant (AdG), PE4, ERC-2011-ADG_20110209
Summary "There has been an immense investment of time, effort and resources in the development of the technologies that enable DNA sequencing in the past 10 years. Despite the significant advances made, all of the current genomic sequencing technologies suffer from two important shortcomings. Firstly, sample preparation is time-consuming and expensive, and requiring a full day for sample preparation for next-generation sequencing experiments. Secondly, sequence information is delivered in short fragments, which are then assembled into a complete genome. Assembly is time-consuming and often results in a highly fragmented genomic sequence and the loss of important information on large-scale structural variation within the genome.
We recently developed a super-resolution DNA mapping technology, which allows us to uniquely study genetic-scale features in genomic length DNA molecules. Labelling the DNA with fluorescent molecules at specific sequences and using high-resolution fluorescence microscopy enabled us to produce a map of a genomic DNA sequence with unparalleled resolution, the so called FLUOROCODE. In this project we aim to extend our methodology to map longer DNA molecules and to include a multi-colour version of the FLUOROCODE that will allow us to read genomic DNA molecules like a barcode and probe DNA methylation status. The sample preparation, DNA labelling and deposition for imaging will be integrated to allow rapid mapping of DNA molecules. At the same time nanopores will be explored as a route to high-throughput DNA mapping.
FLUOROCODE will develop technology that aims to complement the information derived from current DNA sequencing platforms. The technology developed by FLUOROCODE will enable DNA mapping at unprecedented speed and for a fraction of the cost of a typical DNA sequencing project. We aniticipate that our method will find applications in the rapid identification of pathogens and in producing genomic scaffolds to improve genome sequence assembly."
Summary
"There has been an immense investment of time, effort and resources in the development of the technologies that enable DNA sequencing in the past 10 years. Despite the significant advances made, all of the current genomic sequencing technologies suffer from two important shortcomings. Firstly, sample preparation is time-consuming and expensive, and requiring a full day for sample preparation for next-generation sequencing experiments. Secondly, sequence information is delivered in short fragments, which are then assembled into a complete genome. Assembly is time-consuming and often results in a highly fragmented genomic sequence and the loss of important information on large-scale structural variation within the genome.
We recently developed a super-resolution DNA mapping technology, which allows us to uniquely study genetic-scale features in genomic length DNA molecules. Labelling the DNA with fluorescent molecules at specific sequences and using high-resolution fluorescence microscopy enabled us to produce a map of a genomic DNA sequence with unparalleled resolution, the so called FLUOROCODE. In this project we aim to extend our methodology to map longer DNA molecules and to include a multi-colour version of the FLUOROCODE that will allow us to read genomic DNA molecules like a barcode and probe DNA methylation status. The sample preparation, DNA labelling and deposition for imaging will be integrated to allow rapid mapping of DNA molecules. At the same time nanopores will be explored as a route to high-throughput DNA mapping.
FLUOROCODE will develop technology that aims to complement the information derived from current DNA sequencing platforms. The technology developed by FLUOROCODE will enable DNA mapping at unprecedented speed and for a fraction of the cost of a typical DNA sequencing project. We aniticipate that our method will find applications in the rapid identification of pathogens and in producing genomic scaffolds to improve genome sequence assembly."
Max ERC Funding
2 423 160 €
Duration
Start date: 2012-09-01, End date: 2017-08-31
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
