Project acronym 3DCellPhase-
Project In situ Structural Analysis of Molecular Crowding and Phase Separation
Researcher (PI) Julia MAHAMID
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Summary
This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Max ERC Funding
1 228 125 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym 3DEpi
Project Transgenerational epigenetic inheritance of chromatin states : the role of Polycomb and 3D chromosome architecture
Researcher (PI) Giacomo CAVALLI
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS2, ERC-2017-ADG
Summary Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Summary
Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym 3DPROTEINPUZZLES
Project Shape-directed protein assembly design
Researcher (PI) Lars Ingemar ANDRÉ
Host Institution (HI) LUNDS UNIVERSITET
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Summary
Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Max ERC Funding
2 325 292 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym 4D-GenEx
Project Spatio-temporal Organization and Expression of the Genome
Researcher (PI) Antoine COULON
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS2, ERC-2017-STG
Summary This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Summary
This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology.
In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome.
Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes.
Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.
Max ERC Funding
1 499 750 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym Acclimatize
Project Hypothalamic mechanisms of thermal homeostasis and adaptation
Researcher (PI) Jan SIEMENS
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Summary
Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Max ERC Funding
1 902 500 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ACCUPOL
Project Unlimited Growth? A Comparative Analysis of Causes and Consequences of Policy Accumulation
Researcher (PI) Christoph KNILL
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), SH2, ERC-2017-ADG
Summary ACCUPOL systematically analyzes an intuitively well-known, but curiously under-researched phenomenon: policy accumulation. Societal modernization and progress bring about a continuously growing pile of policies in most political systems. At the same time, however, the administrative capacities for implementation are largely stagnant. While being societally desirable in principle, ever-more policies hence may potentially imply less in terms of policy achievements. Whether or not policy accumulation remains at a ‘sustainable’ rate thus crucially affects the long-term output legitimacy of modern democracies.
Given this development, the central focus of ACCUPOL lies on three questions: Do accumulation rates vary across countries and policy sectors? Which factors mitigate policy accumulation? And to what extent is policy accumulation really associated with an increasing prevalence of implementation deficits? In answering these questions, ACCUPOL radically departs from established research traditions in public policy.
First, the project develops new analytical concepts: Rather than relying on individual policy change as the unit of analysis, we consider policy accumulation to assess the growth of policy portfolios over time. In terms of implementation, ACCUPOL takes into account the overall prevalence of implementation deficits in a given sector instead of analyzing the effectiveness of individual implementation processes.
Second, this analytical innovation also implies a paradigmatic theoretical shift. Because existing theories focus on the analysis of individual policies, they are of limited help to understand causes and consequences of policy accumulation. ACCUPOL develops a novel theoretical approach to fill this theoretical gap.
Third, the project provides new empirical evidence on the prevalence of policy accumulation and implementation deficits focusing on 25 OECD countries and two key policy areas (social and environmental policy).
Summary
ACCUPOL systematically analyzes an intuitively well-known, but curiously under-researched phenomenon: policy accumulation. Societal modernization and progress bring about a continuously growing pile of policies in most political systems. At the same time, however, the administrative capacities for implementation are largely stagnant. While being societally desirable in principle, ever-more policies hence may potentially imply less in terms of policy achievements. Whether or not policy accumulation remains at a ‘sustainable’ rate thus crucially affects the long-term output legitimacy of modern democracies.
Given this development, the central focus of ACCUPOL lies on three questions: Do accumulation rates vary across countries and policy sectors? Which factors mitigate policy accumulation? And to what extent is policy accumulation really associated with an increasing prevalence of implementation deficits? In answering these questions, ACCUPOL radically departs from established research traditions in public policy.
First, the project develops new analytical concepts: Rather than relying on individual policy change as the unit of analysis, we consider policy accumulation to assess the growth of policy portfolios over time. In terms of implementation, ACCUPOL takes into account the overall prevalence of implementation deficits in a given sector instead of analyzing the effectiveness of individual implementation processes.
Second, this analytical innovation also implies a paradigmatic theoretical shift. Because existing theories focus on the analysis of individual policies, they are of limited help to understand causes and consequences of policy accumulation. ACCUPOL develops a novel theoretical approach to fill this theoretical gap.
Third, the project provides new empirical evidence on the prevalence of policy accumulation and implementation deficits focusing on 25 OECD countries and two key policy areas (social and environmental policy).
Max ERC Funding
2 359 000 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym ACROSS
Project Australasian Colonization Research: Origins of Seafaring to Sahul
Researcher (PI) Rosemary Helen FARR
Host Institution (HI) UNIVERSITY OF SOUTHAMPTON
Call Details Starting Grant (StG), SH6, ERC-2017-STG
Summary One of the most exciting research questions within archaeology is that of the peopling of Australasia by at least c.50,000 years ago. This represents some of the earliest evidence of modern human colonization outside Africa, yet, even at the greatest sea-level lowstand, this migration would have involved seafaring. It is the maritime nature of this dispersal which makes it so important to questions of technological, cognitive and social human development. These issues have traditionally been the preserve of archaeologists, but with a multidisciplinary approach that embraces cutting-edge marine geophysical, hydrodynamic and archaeogenetic analyses, we now have the opportunity to examine the When, Where, Who and How of the earliest seafaring in world history.
The voyage from Sunda (South East Asia) to Sahul (Australasia) provides evidence for the earliest ‘open water’ crossing in the world. A combination of the sparse number of early archaeological finds and the significant changes in the palaeolandscape and submergence of the broad north western Australian continental shelf, mean that little is known about the routes taken and what these crossings may have entailed.
This project will combine research of the submerged palaeolandscape of the continental shelf to refine our knowledge of the onshore/offshore environment, identify potential submerged prehistoric sites and enhance our understanding of the palaeoshoreline and tidal regime. This will be combined with archaeogenetic research targeting mtDNA and Y-chromosome data to resolve questions of demography and dating.
For the first time this project takes a truly multidisciplinary approach to address the colonization of Sahul, providing an unique opportunity to tackle some of the most important questions about human origins, the relationship between humans and the changing environment, population dynamics and migration, seafaring technology, social organisation and cognition.
Summary
One of the most exciting research questions within archaeology is that of the peopling of Australasia by at least c.50,000 years ago. This represents some of the earliest evidence of modern human colonization outside Africa, yet, even at the greatest sea-level lowstand, this migration would have involved seafaring. It is the maritime nature of this dispersal which makes it so important to questions of technological, cognitive and social human development. These issues have traditionally been the preserve of archaeologists, but with a multidisciplinary approach that embraces cutting-edge marine geophysical, hydrodynamic and archaeogenetic analyses, we now have the opportunity to examine the When, Where, Who and How of the earliest seafaring in world history.
The voyage from Sunda (South East Asia) to Sahul (Australasia) provides evidence for the earliest ‘open water’ crossing in the world. A combination of the sparse number of early archaeological finds and the significant changes in the palaeolandscape and submergence of the broad north western Australian continental shelf, mean that little is known about the routes taken and what these crossings may have entailed.
This project will combine research of the submerged palaeolandscape of the continental shelf to refine our knowledge of the onshore/offshore environment, identify potential submerged prehistoric sites and enhance our understanding of the palaeoshoreline and tidal regime. This will be combined with archaeogenetic research targeting mtDNA and Y-chromosome data to resolve questions of demography and dating.
For the first time this project takes a truly multidisciplinary approach to address the colonization of Sahul, providing an unique opportunity to tackle some of the most important questions about human origins, the relationship between humans and the changing environment, population dynamics and migration, seafaring technology, social organisation and cognition.
Max ERC Funding
1 134 928 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym activeFly
Project Circuit mechanisms of self-movement estimation during walking
Researcher (PI) M Eugenia CHIAPPE
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
Summary
The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym AdaptiveResponse
Project The evolution of adaptive response mechanisms
Researcher (PI) Franz WEISSING
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Advanced Grant (AdG), LS8, ERC-2017-ADG
Summary In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Summary
In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym AfricanNeo
Project The African Neolithic: A genetic perspective
Researcher (PI) Carina SCHLEBUSCH
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), SH6, ERC-2017-STG
Summary The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Summary
The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
