Project acronym AGELESS
Project Comparative genomics / ‘wildlife’ transcriptomics uncovers the mechanisms of halted ageing in mammals
Researcher (PI) Emma Teeling
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary "Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."
Summary
"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."
Max ERC Funding
1 499 768 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym CholAminCo
Project Synergy and antagonism of cholinergic and dopaminergic systems in associative learning
Researcher (PI) Balazs Gyoergy HANGYA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Summary
Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Max ERC Funding
1 499 463 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym DOSE
Project Dosage sensitive genes in evolution and disease
Researcher (PI) Aoife Mclysaght
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity.
In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci.
Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease.
This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.
Summary
Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity.
In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci.
Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease.
This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.
Max ERC Funding
1 358 534 €
Duration
Start date: 2013-01-01, End date: 2018-12-31
Project acronym FRONTHAL
Project Specificity of cortico-thalamic interactions and its role in frontal cortical functions
Researcher (PI) Laszlo ACSADY
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Summary
Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Max ERC Funding
1 597 575 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym GENECLOCKS
Project Reconstructing a dated tree of life using phylogenetic incongruence
Researcher (PI) Gergely Janos SZOLLOSI
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Summary
With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Max ERC Funding
1 453 542 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym HybridSolarFuels
Project Efficient Photoelectrochemical Transformation of CO2 to Useful Fuels on Nanostructured Hybrid Electrodes
Researcher (PI) Csaba JANAKY
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Starting Grant (StG), PE4, ERC-2016-STG
Summary Given that CO2 is a greenhouse gas, using the energy of sunlight to convert CO2 to transportation fuels (such as methanol) represents a value-added approach to the simultaneous generation of alternative fuels and environmental remediation of carbon emissions. Photoelectrochemistry has been proven to be a useful avenue for solar water splitting. CO2 reduction, however, is multi-electron in nature (e.g., 6 e- to methanol) with considerable kinetic barriers to electron transfer. It therefore requires the use of carefully designed electrode surfaces to accelerate e- transfer rates to levels that make practical sense. In addition, novel flow-cell configurations have to be designed to overcome mass transport limitations of this reaction.
We are going to design and assemble nanostructured hybrid materials to be simultaneously applied as both adsorber and cathode-material to photoelectrochemically convert CO2 to valuable liquid fuels. The three main goals of this project are to (i) gain fundamental understanding of morphological-, size-, and surface functional group effects on the photoelectrochemical (PEC) behavior at the nanoscale (ii) design and synthesize new functional hybrid materials for PEC CO2 reduction, (iii) develop flow-reactors for PEC CO2 reduction. Rationally designed hybrid nanostructures of large surface area p-type semiconductors (e.g., SiC, CuMO2, or CuPbI3) and N-containing conducting polymers (e.g., polyaniline-based custom designed polymers) will be responsible for: (i) higher photocurrents due to facile charge transfer and better light absorption (ii) higher selectivity towards the formation of liquid fuels due to the adsorption of CO2 on the photocathode (iii) better stability of the photocathode. The challenges are great, but the possible rewards are enormous: performing CO2 adsorption and reduction on the same system may lead to PEC cells which can be deployed directly at the source point of CO2, which would go well beyond the state-of-the-art.
Summary
Given that CO2 is a greenhouse gas, using the energy of sunlight to convert CO2 to transportation fuels (such as methanol) represents a value-added approach to the simultaneous generation of alternative fuels and environmental remediation of carbon emissions. Photoelectrochemistry has been proven to be a useful avenue for solar water splitting. CO2 reduction, however, is multi-electron in nature (e.g., 6 e- to methanol) with considerable kinetic barriers to electron transfer. It therefore requires the use of carefully designed electrode surfaces to accelerate e- transfer rates to levels that make practical sense. In addition, novel flow-cell configurations have to be designed to overcome mass transport limitations of this reaction.
We are going to design and assemble nanostructured hybrid materials to be simultaneously applied as both adsorber and cathode-material to photoelectrochemically convert CO2 to valuable liquid fuels. The three main goals of this project are to (i) gain fundamental understanding of morphological-, size-, and surface functional group effects on the photoelectrochemical (PEC) behavior at the nanoscale (ii) design and synthesize new functional hybrid materials for PEC CO2 reduction, (iii) develop flow-reactors for PEC CO2 reduction. Rationally designed hybrid nanostructures of large surface area p-type semiconductors (e.g., SiC, CuMO2, or CuPbI3) and N-containing conducting polymers (e.g., polyaniline-based custom designed polymers) will be responsible for: (i) higher photocurrents due to facile charge transfer and better light absorption (ii) higher selectivity towards the formation of liquid fuels due to the adsorption of CO2 on the photocathode (iii) better stability of the photocathode. The challenges are great, but the possible rewards are enormous: performing CO2 adsorption and reduction on the same system may lead to PEC cells which can be deployed directly at the source point of CO2, which would go well beyond the state-of-the-art.
Max ERC Funding
1 498 750 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym iHEAR
Project Investigating the meanings and mechanisms of psychotic experiences in young people: a novel, mixed-methods approach
Researcher (PI) Mary CANNON
Host Institution (HI) ROYAL COLLEGE OF SURGEONS IN IRELAND
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Up to one fifth of young people have had the experience of psychotic symptoms, such as hearing voices when there is no-one around, or seeing visions. We now know that young people who experience these symptoms are at increased risk of developing psychotic disorders in adulthood. We also know that these young people are at higher risk of a range of co-morbid disorders such as depression and anxiety, and particularly suicidal behaviours. On the other hand, many of these young people will remain well and, for them, the psychotic experiences were merely a transitory phenomenon.
Childhood trauma is known to be associated with increased risk for psychotic symptoms and is a promising target for intervention. However we do not yet know enough about what types or timing of stressors are involved in the pathogenesis of psychotic symptoms, nor the mechanism by which early life stress may lead to changes in brain structure and function resulting in symptoms such as hallucinations. We also need to be able to identify those young people who will benefit most from intervention.
This ground-breaking, multi-disciplinary programme of work sets out to address these issues by drawing together epidemiology, social science, anthropology and neuroscience to devise a comprehensive programme of work examining the relationship between early life stress and psychotic symptoms among young people.
Designed as three inter-related work packages, this iHEAR programme will exploit a large population-based cohort and will capitalise on my existing unique cohort of young people, who were known to have experienced psychotic symptoms in childhood, as they enter young adulthood. This iHEAR programme will result in new information which will allow the development of innovative interventions to prevent or pre-empt severe mental illness in later life.
Summary
Up to one fifth of young people have had the experience of psychotic symptoms, such as hearing voices when there is no-one around, or seeing visions. We now know that young people who experience these symptoms are at increased risk of developing psychotic disorders in adulthood. We also know that these young people are at higher risk of a range of co-morbid disorders such as depression and anxiety, and particularly suicidal behaviours. On the other hand, many of these young people will remain well and, for them, the psychotic experiences were merely a transitory phenomenon.
Childhood trauma is known to be associated with increased risk for psychotic symptoms and is a promising target for intervention. However we do not yet know enough about what types or timing of stressors are involved in the pathogenesis of psychotic symptoms, nor the mechanism by which early life stress may lead to changes in brain structure and function resulting in symptoms such as hallucinations. We also need to be able to identify those young people who will benefit most from intervention.
This ground-breaking, multi-disciplinary programme of work sets out to address these issues by drawing together epidemiology, social science, anthropology and neuroscience to devise a comprehensive programme of work examining the relationship between early life stress and psychotic symptoms among young people.
Designed as three inter-related work packages, this iHEAR programme will exploit a large population-based cohort and will capitalise on my existing unique cohort of young people, who were known to have experienced psychotic symptoms in childhood, as they enter young adulthood. This iHEAR programme will result in new information which will allow the development of innovative interventions to prevent or pre-empt severe mental illness in later life.
Max ERC Funding
1 781 623 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym MEME
Project Memory Engram Maintenance and Expression
Researcher (PI) Tomas RYAN
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The goal of this project is to understand how specific memory engrams are physically stored in the brain. Connectionist theories of memory storage have guided research into the neuroscience of memory for over a half century, but have received little direct proof due to experimental limitations. The major confound that has limited direct testing of such theories has been an inability to identify the cells and circuits that store specific memories. Memory engram technology, which allows the tagging and in vivo manipulation of specific engram cells, has recently allowed us to overcome this empirical limitation and has revolutionised the way memory can be studied in rodent models. Based on our research it is now known that sparse populations of hippocampal neurons that were active during a defined learning experience are both sufficient and necessary for retrieval of specific contextual memories. More recently we have established that hippocampal engram cells preferentially synapse directly onto postsynaptic engram cells. This “engram cell connectivity” could provide the neurobiological substrate for the storage of multimodal memories through a distributed engram circuit. However it is currently unknown whether engram cell connectivity itself is important for memory function. The proposed integrative neuroscience project will employ inter-disciplinary methods to directly probe the importance of engram cell connectivity for memory retrieval, storage, and encoding. The outcomes will directly inform a novel and comprehensive neurobiological model of memory engram storage.
Summary
The goal of this project is to understand how specific memory engrams are physically stored in the brain. Connectionist theories of memory storage have guided research into the neuroscience of memory for over a half century, but have received little direct proof due to experimental limitations. The major confound that has limited direct testing of such theories has been an inability to identify the cells and circuits that store specific memories. Memory engram technology, which allows the tagging and in vivo manipulation of specific engram cells, has recently allowed us to overcome this empirical limitation and has revolutionised the way memory can be studied in rodent models. Based on our research it is now known that sparse populations of hippocampal neurons that were active during a defined learning experience are both sufficient and necessary for retrieval of specific contextual memories. More recently we have established that hippocampal engram cells preferentially synapse directly onto postsynaptic engram cells. This “engram cell connectivity” could provide the neurobiological substrate for the storage of multimodal memories through a distributed engram circuit. However it is currently unknown whether engram cell connectivity itself is important for memory function. The proposed integrative neuroscience project will employ inter-disciplinary methods to directly probe the importance of engram cell connectivity for memory retrieval, storage, and encoding. The outcomes will directly inform a novel and comprehensive neurobiological model of memory engram storage.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym MicroCONtACT
Project Microglial control of neuronal activity in the healthy and the injured brain
Researcher (PI) Adam DENES
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Summary
Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym OCULUS
Project A radical approach for improved glaucoma treatment
Researcher (PI) Peter Humphries
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary Open angle glaucoma (OAG) is the second leading cause of world blindness. Treatments involving topically applied pressure-reducing medications or surgery targeting ocular drainage channels are effective, although significant complications exist. We propose to address the hypothesis that it is possible to develop a radical approach to management of intraocular pressure employing an AAV-mediated system for increasing the permeability of Schlemm’s canal endothelial cells (SCEC), based on published supportive data from this laboratory showing that RNAi-mediated down regulation of mRNA encoding components of tight junctions of neuronal vascular endothelia induces increased cell permeability, a process which has been used to validate a procedure for acute treatment of neuronal edema. While tight junctions of neuronal vascular endothelial cells have been extensively studied and comprise of a series of up to 30 protein components, less is known of the organization of adherence mechanisms of SCEC, although electron- and immunofluorescence microscopy show the presence of tight junctions. We propose a comprehensive analysis of tight junction protein expression in SCEC in vitro. In vivo studies will involve introduction of AAV vectors into the anterior chamber of the eye in rodent models of elevated IOP. The vectors will be designed to express shRNAs targeting a variety of tight junction transcripts expressed in SCEC using an inducible system. The effect of RNAi-mediated increase in the permeability of SCEC will be assessed using aqueous humour outflow measurement methods and we will also explore the utility of high resolution and diffusion-weighted MRI for this purpose, which may prove to be a simpler, non-invasive and clinically relevant method. This research will provide further fundamental insights into the mechanisms of ocular pressure maintenance and could provide benefit to those patients not responsive to conventional means of therapy.
Summary
Open angle glaucoma (OAG) is the second leading cause of world blindness. Treatments involving topically applied pressure-reducing medications or surgery targeting ocular drainage channels are effective, although significant complications exist. We propose to address the hypothesis that it is possible to develop a radical approach to management of intraocular pressure employing an AAV-mediated system for increasing the permeability of Schlemm’s canal endothelial cells (SCEC), based on published supportive data from this laboratory showing that RNAi-mediated down regulation of mRNA encoding components of tight junctions of neuronal vascular endothelia induces increased cell permeability, a process which has been used to validate a procedure for acute treatment of neuronal edema. While tight junctions of neuronal vascular endothelial cells have been extensively studied and comprise of a series of up to 30 protein components, less is known of the organization of adherence mechanisms of SCEC, although electron- and immunofluorescence microscopy show the presence of tight junctions. We propose a comprehensive analysis of tight junction protein expression in SCEC in vitro. In vivo studies will involve introduction of AAV vectors into the anterior chamber of the eye in rodent models of elevated IOP. The vectors will be designed to express shRNAs targeting a variety of tight junction transcripts expressed in SCEC using an inducible system. The effect of RNAi-mediated increase in the permeability of SCEC will be assessed using aqueous humour outflow measurement methods and we will also explore the utility of high resolution and diffusion-weighted MRI for this purpose, which may prove to be a simpler, non-invasive and clinically relevant method. This research will provide further fundamental insights into the mechanisms of ocular pressure maintenance and could provide benefit to those patients not responsive to conventional means of therapy.
Max ERC Funding
2 499 838 €
Duration
Start date: 2013-04-01, End date: 2018-09-30
