Project acronym BrainNanoFlow
Project Nanoscale dynamics in the extracellular space of the brain in vivo
Researcher (PI) Juan Alberto VARELA
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Country United Kingdom
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Summary
Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Max ERC Funding
1 552 948 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BRAINPOWER
Project Brain energy supply and the consequences of its failure
Researcher (PI) David Ian Attwell
Host Institution (HI) University College London
Country United Kingdom
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Summary
Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Max ERC Funding
2 499 947 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym ChaperoneRegulome
Project ChaperoneRegulome: Understanding cell-type-specificity of chaperone regulation
Researcher (PI) Ritwick SAWARKAR
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Summary
Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Max ERC Funding
1 992 500 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym CHROMOCOND
Project A molecular view of chromosome condensation
Researcher (PI) Frank Uhlmann
Host Institution (HI) CANCER RESEARCH UK LBG
Country United Kingdom
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.
Summary
Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.
Max ERC Funding
2 076 126 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym CMR
Project Cosmic ray acceleration, magnetic field and radiation hydrodynamics
Researcher (PI) Anthony Raymond Bell
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), PE9, ERC-2009-AdG
Summary Diffusive shock acceleration is widely acknowledged as the most likely source of cosmic rays and high energy particles. The basic macroscopic theory of how cosmic rays gain energy during multiple shock crossings is well known, but the microphysics of the interaction between cosmic rays (CR) and the MHD background fluid remained poorly understood before the recent discovery of a new non-resonant instability by which the CR precursor could greatly amplify the ambient magnetic field. The aims of the project are: 1) to develop the first self-consistent non-linear simulation of the CR/MHD interaction; to calculate the magnitude of the saturated magnetic field and the maximum energy to which CR are accelerated. We will characterise the structure of the amplified magnetic field and compare it with x-ray observations of the time-evolving outer shock of supernova remnants (SNR). We will investigate the effect of various orientations of the shock relative to the ambient magnetic field, the effect of non-diffusive transport on the energy spectrum and CR escape from the SNR, and how these match observation. 2) to extend the simulation to relativistic shocks as found in gamma-ray bursts (GRB) and active galactic nuclei (AGN); to establish whether the non-resonant instability operates effectively at relativistic shock velocities, whether it explains the large magnetic field found in GRB, and determine the maximum CR energy achieved by relativistic shocks. 3) to investigate high density shocks in GRB, x-ray flashes (XRF) and supernovae (SN) where radiative processes, pair production and other particle/photon and particle/particle interactions are important. We shall investigate CR acceleration on SN shock breakout and very young SNR as a possible source of very high energy CR.
Summary
Diffusive shock acceleration is widely acknowledged as the most likely source of cosmic rays and high energy particles. The basic macroscopic theory of how cosmic rays gain energy during multiple shock crossings is well known, but the microphysics of the interaction between cosmic rays (CR) and the MHD background fluid remained poorly understood before the recent discovery of a new non-resonant instability by which the CR precursor could greatly amplify the ambient magnetic field. The aims of the project are: 1) to develop the first self-consistent non-linear simulation of the CR/MHD interaction; to calculate the magnitude of the saturated magnetic field and the maximum energy to which CR are accelerated. We will characterise the structure of the amplified magnetic field and compare it with x-ray observations of the time-evolving outer shock of supernova remnants (SNR). We will investigate the effect of various orientations of the shock relative to the ambient magnetic field, the effect of non-diffusive transport on the energy spectrum and CR escape from the SNR, and how these match observation. 2) to extend the simulation to relativistic shocks as found in gamma-ray bursts (GRB) and active galactic nuclei (AGN); to establish whether the non-resonant instability operates effectively at relativistic shock velocities, whether it explains the large magnetic field found in GRB, and determine the maximum CR energy achieved by relativistic shocks. 3) to investigate high density shocks in GRB, x-ray flashes (XRF) and supernovae (SN) where radiative processes, pair production and other particle/photon and particle/particle interactions are important. We shall investigate CR acceleration on SN shock breakout and very young SNR as a possible source of very high energy CR.
Max ERC Funding
900 024 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym COGS
Project Capitalizing on Gravitational Shear
Researcher (PI) Sarah Louise Bridle
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Country United Kingdom
Call Details Starting Grant (StG), PE9, ERC-2009-StG
Summary Our Universe appears to be filled with mysterious ingredients: 25 per cent appears to be dark matter, perhaps an as-yet undiscovered particle, and 70 per cent seems to be a bizarre fluid, dubbed dark energy, for which there is no satisfactory theory. Solving the dark energy problem is the most pressing question in cosmology today. It is possible that dark energy does not exist at all, and instead Einstein s theory of General Relativity is flawed. Cosmologists hope to measure the properties of the dark energy using the next generation of cosmological observations, in which I am playing a leading role. I believe the most promising technique to crack the dark energy problem is gravitational shear, in which images of distant galaxies are distorted as they pass through the intervening dark matter distribution. Analysis of the distortions allows a map of the dark matter to be reconstructed; by examining the dark matter distribution we uncover the nature of the apparent dark energy. However to capitalize on the great potential of gravitational shear we must measure incredibly small image distortions in the presence of much larger image modifications that occur in the measurement process. I am proposing a fresh look at this problem using an inter-disciplinary approach in collaboration with computer scientists. This grant would enable my team to play a central role in the key results from the upcoming Dark Energy Survey. We would further capitalize on the gravitational shear signal by moving away from the current dark energy bandwagon by instead focusing on testing General Relativity using novel approaches. Our work will produce results which will lead the next Einstein to solve the biggest puzzle in cosmology, and arguably physics.
Summary
Our Universe appears to be filled with mysterious ingredients: 25 per cent appears to be dark matter, perhaps an as-yet undiscovered particle, and 70 per cent seems to be a bizarre fluid, dubbed dark energy, for which there is no satisfactory theory. Solving the dark energy problem is the most pressing question in cosmology today. It is possible that dark energy does not exist at all, and instead Einstein s theory of General Relativity is flawed. Cosmologists hope to measure the properties of the dark energy using the next generation of cosmological observations, in which I am playing a leading role. I believe the most promising technique to crack the dark energy problem is gravitational shear, in which images of distant galaxies are distorted as they pass through the intervening dark matter distribution. Analysis of the distortions allows a map of the dark matter to be reconstructed; by examining the dark matter distribution we uncover the nature of the apparent dark energy. However to capitalize on the great potential of gravitational shear we must measure incredibly small image distortions in the presence of much larger image modifications that occur in the measurement process. I am proposing a fresh look at this problem using an inter-disciplinary approach in collaboration with computer scientists. This grant would enable my team to play a central role in the key results from the upcoming Dark Energy Survey. We would further capitalize on the gravitational shear signal by moving away from the current dark energy bandwagon by instead focusing on testing General Relativity using novel approaches. Our work will produce results which will lead the next Einstein to solve the biggest puzzle in cosmology, and arguably physics.
Max ERC Funding
1 400 000 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym CULTRWORLD
Project The evolution of cultural norms in real world settings
Researcher (PI) Ruth Helen Mace
Host Institution (HI) University College London
Country United Kingdom
Call Details Advanced Grant (AdG), SH4, ERC-2009-AdG
Summary An intense debate is raging within evolutionary anthropology as to whether the evolution of human behaviour is driven by selection pressure on the individual or on the group. Until recently there was consensus amongst evolutionary biologists and evolutionary anthropologists that natural selection caused behaviours to evolve that benefit the individual or close kin. However the idea that cultural behaviours that favour the group can evolve, even at the expense of individual well-being, is now being supported by some evolutionary anthropologists and economists. Models of cultural group selection rely on patterns of cultural transmission that maintain differences between cultural groups, because either decisions are based on what most others in the group do, or non-conformists are punished in some way. If such biased transmission occurs, then humans may be following a unique evolutionary trajectory towards extreme sociality; such models potentially explain behaviours such as altruism towards non-relatives or limiting your reproductive rate. However, relevant empirical evidence from real world populations, concerning behaviour that potentially influences reproductive success, is almost entirely lacking. The projects proposed here are designed to help fill that gap. In micro-evolutionary studies we will seek evidence for the patterns cultural transmission or social learning that enable cultural group selection to act, and ask how these processes depend on properties of the community, and thus how robust are they to the demographic and societal changes that accompany modernisation. These include studies of the spread of modern contraception through communities; and studies of punishment of selfish players in economic games. In macro-evolutionary studies, we will use phylogenetic cross-cultural comparative methods to show how different cultural traits change over the long term, and ask whether social or ecological variables are driving that cultural change.
Summary
An intense debate is raging within evolutionary anthropology as to whether the evolution of human behaviour is driven by selection pressure on the individual or on the group. Until recently there was consensus amongst evolutionary biologists and evolutionary anthropologists that natural selection caused behaviours to evolve that benefit the individual or close kin. However the idea that cultural behaviours that favour the group can evolve, even at the expense of individual well-being, is now being supported by some evolutionary anthropologists and economists. Models of cultural group selection rely on patterns of cultural transmission that maintain differences between cultural groups, because either decisions are based on what most others in the group do, or non-conformists are punished in some way. If such biased transmission occurs, then humans may be following a unique evolutionary trajectory towards extreme sociality; such models potentially explain behaviours such as altruism towards non-relatives or limiting your reproductive rate. However, relevant empirical evidence from real world populations, concerning behaviour that potentially influences reproductive success, is almost entirely lacking. The projects proposed here are designed to help fill that gap. In micro-evolutionary studies we will seek evidence for the patterns cultural transmission or social learning that enable cultural group selection to act, and ask how these processes depend on properties of the community, and thus how robust are they to the demographic and societal changes that accompany modernisation. These include studies of the spread of modern contraception through communities; and studies of punishment of selfish players in economic games. In macro-evolutionary studies, we will use phylogenetic cross-cultural comparative methods to show how different cultural traits change over the long term, and ask whether social or ecological variables are driving that cultural change.
Max ERC Funding
1 801 978 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym DENDRITE
Project Cellular and circuit determinants of dendritic computation
Researcher (PI) Michael Andreas Hausser
Host Institution (HI) University College London
Country United Kingdom
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.
Summary
What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.
Max ERC Funding
2 416 078 €
Duration
Start date: 2010-06-01, End date: 2016-05-31
Project acronym DEVMEM
Project Learning to remember: the development of the neural mechanisms supporting memory processing.
Researcher (PI) Francesca CACUCCI
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary The ability to form and store memories allows organisms to learn from the past and imagine the future: it is a crucial mechanism underlying flexible and adaptive behaviour. The aim of this proposal is to identify the circuit mechanisms underlying our ability to learn and remember, by tracking the ontogenesis of memory processing. Importantly, we are not born with a fully functioning memory system: generally, adults cannot recollect any events from before their third birthday (‘infantile amnesia’). There are several accounts as to the source of this mnemonic deficit, each placing emphasis on impairments of specific processes (encoding, consolidation, retrieval). However, a general weakness in the study of memory ontogeny is the lack of neural data describing the activity of memory-related circuits during development. To directly address this knowledge gap, we propose to study the ontogeny of brain-wide hippocampus-centred memory networks in the rat. We will study to which extent memory expression relies on spatial signalling, delineate the role of sleep in memory consolidation, determine how hippocampal planning-related neuronal activity influences memory processing, understand whether the rapid forgetting observed in development is due to interference, and explore interactions between the hippocampus, pre-frontal and striatal circuits in orchestrating memory emergence. We are best placed to deliver this ambitious experimental plan due to our extensive experience of in vivo recording in developing rats which we will couple with the application of recently emerged technologies (2-photon imaging, high density electrophysiology, chemogenetic manipulation of neural activity). As our studies of the development of hippocampal spatial representations have delivered powerful insights into their adult function, we expect the work outlined here to critically advance our understanding not only of development, but also of healthy memory processing in adulthood.
Summary
The ability to form and store memories allows organisms to learn from the past and imagine the future: it is a crucial mechanism underlying flexible and adaptive behaviour. The aim of this proposal is to identify the circuit mechanisms underlying our ability to learn and remember, by tracking the ontogenesis of memory processing. Importantly, we are not born with a fully functioning memory system: generally, adults cannot recollect any events from before their third birthday (‘infantile amnesia’). There are several accounts as to the source of this mnemonic deficit, each placing emphasis on impairments of specific processes (encoding, consolidation, retrieval). However, a general weakness in the study of memory ontogeny is the lack of neural data describing the activity of memory-related circuits during development. To directly address this knowledge gap, we propose to study the ontogeny of brain-wide hippocampus-centred memory networks in the rat. We will study to which extent memory expression relies on spatial signalling, delineate the role of sleep in memory consolidation, determine how hippocampal planning-related neuronal activity influences memory processing, understand whether the rapid forgetting observed in development is due to interference, and explore interactions between the hippocampus, pre-frontal and striatal circuits in orchestrating memory emergence. We are best placed to deliver this ambitious experimental plan due to our extensive experience of in vivo recording in developing rats which we will couple with the application of recently emerged technologies (2-photon imaging, high density electrophysiology, chemogenetic manipulation of neural activity). As our studies of the development of hippocampal spatial representations have delivered powerful insights into their adult function, we expect the work outlined here to critically advance our understanding not only of development, but also of healthy memory processing in adulthood.
Max ERC Funding
1 999 520 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym DISKtoHALO
Project From the accretion disk to the cluster halo: the multi-scale physics of black hole feedback
Researcher (PI) Christopher REYNOLDS
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Advanced Grant (AdG), PE9, ERC-2018-ADG
Summary It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
Summary
It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
Max ERC Funding
2 489 918 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
