Project acronym CELPRED
Project Circuit elements of the cortical circuit for predictive processing
Researcher (PI) Georg KELLER
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Summary
One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym IC-CCD-qHSC
Project Intrapopulation communication and collective cell decisions of hematopoietic stem cells
Researcher (PI) Cesar NOMBELA
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Consolidator Grant (CoG), LS3, ERC-2019-COG
Summary Hematopoietic stem cells (HSCs) contribute to blood cell production throughout life and are found at rare, yet tightly regulated frequencies in adult bone marrow (BM). During embryonic and postnatal development, HSCs expand through continuous self-renewing proliferation. Upon entry into adulthood the vast majority of HSCs synchronously convert to a quiescent state. From then on, at any given moment very few HSCs are found in active stages of cell cycle, which suffices to compensate basal HSC loss due to differentiation or cell death. Since proliferation rates of individual HSCs are heterogeneous, entry and exit from cell cycle need to be coordinated at the level of the HSC pool. To date, the mechanisms that orchestrate this collective proliferative behavior and effectively control the maintenance of homeostatic HSC numbers remain unknown. In preliminary work for this project we have customized a pipeline that combines 3D microscopy, deep learning-based image analysis and spatial statistics. Using these tools, we observed that despite showing broad spatial heterogeneity, HSCs tend to cluster and accumulate in relatively large regions of the BM. We now postulate that molecular crosstalk between proximal HSCs enables them to perceive their local densities and triggers collective regulation of HSC function to preserve homeostasis. Through a multidisciplinary approach involving high-level microscopy, spatial analyses, comprehensive metabolomic profiling and single-cell transcriptomics we aim to 1) characterize the basic anatomical and functional features of spatial dependencies between HSCs 2) study the potential role of quorum-sensing mechanisms in HSC crosstalk and 3) investigate if competition for molecular resources in local neighborhoods contributes to maintenance of HSC homeostasis. Our research has the potential to unravel novel complex forms of cellular interplay and substantially advance our understanding of hematopoietic tissue organization.
Summary
Hematopoietic stem cells (HSCs) contribute to blood cell production throughout life and are found at rare, yet tightly regulated frequencies in adult bone marrow (BM). During embryonic and postnatal development, HSCs expand through continuous self-renewing proliferation. Upon entry into adulthood the vast majority of HSCs synchronously convert to a quiescent state. From then on, at any given moment very few HSCs are found in active stages of cell cycle, which suffices to compensate basal HSC loss due to differentiation or cell death. Since proliferation rates of individual HSCs are heterogeneous, entry and exit from cell cycle need to be coordinated at the level of the HSC pool. To date, the mechanisms that orchestrate this collective proliferative behavior and effectively control the maintenance of homeostatic HSC numbers remain unknown. In preliminary work for this project we have customized a pipeline that combines 3D microscopy, deep learning-based image analysis and spatial statistics. Using these tools, we observed that despite showing broad spatial heterogeneity, HSCs tend to cluster and accumulate in relatively large regions of the BM. We now postulate that molecular crosstalk between proximal HSCs enables them to perceive their local densities and triggers collective regulation of HSC function to preserve homeostasis. Through a multidisciplinary approach involving high-level microscopy, spatial analyses, comprehensive metabolomic profiling and single-cell transcriptomics we aim to 1) characterize the basic anatomical and functional features of spatial dependencies between HSCs 2) study the potential role of quorum-sensing mechanisms in HSC crosstalk and 3) investigate if competition for molecular resources in local neighborhoods contributes to maintenance of HSC homeostasis. Our research has the potential to unravel novel complex forms of cellular interplay and substantially advance our understanding of hematopoietic tissue organization.
Max ERC Funding
2 312 500 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym No Sex No Conflict
Project Evolutionary Consequences of Arrested Genomic Conflict in Asexual Species
Researcher (PI) Tanja SCHWANDER
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Consolidator Grant (CoG), LS8, ERC-2019-COG
Summary Genomic conflicts are major drivers of evolutionary innovation and play an increasingly recognized role in human disease. Intra-genomic conflicts arise because self-promoting elements such as driving centromeres or transposable elements (TEs) can spread in a population without increasing the fitness of their carriers. Inter-genomic conflicts arise when genes have opposite fitness effects in different carriers, as is the case for genes underlying traits with distinct optimal values in males and females. Here I propose to use asexual species as a novel system to studying intra- and inter-genomic conflicts. Because there is no recombination or segregation under asexual reproduction, intra-genomic conflict disappears as the interests of all genetic elements become aligned with those of their host. This allows us to test the predictions that intra-genomic conflict drives the evolution of TE virulence, centromeres, and centromere-binding proteins. Furthermore, because asexual species are comprised of only females, male phenotypes are no longer under selection and sexual conflict over optimal trait values therefore disappears. This proposal leverages the replicated loss of conflicts in independently evolved asexual lineages of Timema stick insects to identify conflict driven aspects of genomic and phenotypic evolution in sexual species. Because Timema have an XX:XO sex determination system, males can be recovered from asexual lineages via X-chromosome losses. This allows for the study of male reproductive traits, sexual dimorphism and sex-biased gene expression in species where selection has been acting solely on females for prolonged time periods, and for the identification of traits and biological processes subject to sexual conflict. By combining phenotypic, experimental and next-generation sequencing approaches, we will generate a cohesive understanding of how intra- and inter-genomic conflict shape phenotype and genome evolution.
Summary
Genomic conflicts are major drivers of evolutionary innovation and play an increasingly recognized role in human disease. Intra-genomic conflicts arise because self-promoting elements such as driving centromeres or transposable elements (TEs) can spread in a population without increasing the fitness of their carriers. Inter-genomic conflicts arise when genes have opposite fitness effects in different carriers, as is the case for genes underlying traits with distinct optimal values in males and females. Here I propose to use asexual species as a novel system to studying intra- and inter-genomic conflicts. Because there is no recombination or segregation under asexual reproduction, intra-genomic conflict disappears as the interests of all genetic elements become aligned with those of their host. This allows us to test the predictions that intra-genomic conflict drives the evolution of TE virulence, centromeres, and centromere-binding proteins. Furthermore, because asexual species are comprised of only females, male phenotypes are no longer under selection and sexual conflict over optimal trait values therefore disappears. This proposal leverages the replicated loss of conflicts in independently evolved asexual lineages of Timema stick insects to identify conflict driven aspects of genomic and phenotypic evolution in sexual species. Because Timema have an XX:XO sex determination system, males can be recovered from asexual lineages via X-chromosome losses. This allows for the study of male reproductive traits, sexual dimorphism and sex-biased gene expression in species where selection has been acting solely on females for prolonged time periods, and for the identification of traits and biological processes subject to sexual conflict. By combining phenotypic, experimental and next-generation sequencing approaches, we will generate a cohesive understanding of how intra- and inter-genomic conflict shape phenotype and genome evolution.
Max ERC Funding
1 989 769 €
Duration
Start date: 2020-04-01, End date: 2025-03-31
Project acronym Proteomes-in-3D
Project Three-dimensional dynamic views of proteomes as a novel readout for physiological and pathological alterations
Researcher (PI) Paola PICOTTI
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Consolidator Grant (CoG), LS2, ERC-2019-COG
Summary Protein expression screens are routinely used to identify biological processes deregulated upon disease development or upon specific cellular perturbations. Generating molecular hypotheses from these ‘omic data remains challenging, however, and many molecular events that modulate protein function do not involve altered protein levels. With this project, I propose a new paradigm. I propose that by measuring altered structures of proteins on a global scale, we can capture altered functional states of proteins and proteomes. I propose that the new approach will support the generation of testable molecular hypotheses from global data and the development of new frameworks for the modelling of biological systems.
Building on a unique mass spectrometric approach my lab developed, which captures protein structural changes on a proteome-wide scale, we will assess the performance of the global structural readout at analyzing complex phenotypes. We will apply it to a biomedical problem of interest to my lab: the functional and pathological implications of protein aggregates or superassemblies (SAs).
Protein aggregates form not only during disease but also under physiological conditions. These structures regulate important normal processes and contribute to cellular architecture. Using the new structural approach, we will identify and characterize networks of novel functional SAs in E. coli, mouse, and human proteomes. We will assess how genomic variation, environment and age modulate protein structures and SA assembly and how SAs are linked to phenotypes. Last, we will translate our approach to a clinical setting and ask whether altered protein structures can serve as biomarkers of disease, specifically Parkinson’s disease and how SAs underlie Parkinson’s subtypes. We will collect the wealth of dynamic structural data generated through this project into an Atlas of Structural Proteome Dynamics and use the data to shed new light on features of the structural proteome.
Summary
Protein expression screens are routinely used to identify biological processes deregulated upon disease development or upon specific cellular perturbations. Generating molecular hypotheses from these ‘omic data remains challenging, however, and many molecular events that modulate protein function do not involve altered protein levels. With this project, I propose a new paradigm. I propose that by measuring altered structures of proteins on a global scale, we can capture altered functional states of proteins and proteomes. I propose that the new approach will support the generation of testable molecular hypotheses from global data and the development of new frameworks for the modelling of biological systems.
Building on a unique mass spectrometric approach my lab developed, which captures protein structural changes on a proteome-wide scale, we will assess the performance of the global structural readout at analyzing complex phenotypes. We will apply it to a biomedical problem of interest to my lab: the functional and pathological implications of protein aggregates or superassemblies (SAs).
Protein aggregates form not only during disease but also under physiological conditions. These structures regulate important normal processes and contribute to cellular architecture. Using the new structural approach, we will identify and characterize networks of novel functional SAs in E. coli, mouse, and human proteomes. We will assess how genomic variation, environment and age modulate protein structures and SA assembly and how SAs are linked to phenotypes. Last, we will translate our approach to a clinical setting and ask whether altered protein structures can serve as biomarkers of disease, specifically Parkinson’s disease and how SAs underlie Parkinson’s subtypes. We will collect the wealth of dynamic structural data generated through this project into an Atlas of Structural Proteome Dynamics and use the data to shed new light on features of the structural proteome.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym SNUGly
Project Systems-level novel understanding of anti-glycan immunity
Researcher (PI) Emma Wetter Slack
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Consolidator Grant (CoG), LS6, ERC-2019-COG
Summary "Intestinal bacteria have an enormous influence on health, both in the form of major pathogens and as major constituents of the microbiota. We have demonstrated that high-affinity secretory antibodies (sIgA) offer huge potential to protect from infection and to manipulate microbiota composition. However, designing good oral vaccines to induce high-affinity sIgA is a compound problem. Most protective anti-bacterial sIgA targets bacterial glycans, requiring an understanding of inherently difficult glycan biochemistry. We also need to deliver intact antigen via the highly degradative environment of the intestine. Whole-cell inactivated oral vaccines can induce high-affinity sIgA against some glycan structures, but we have an incomplete picture of what determines the success/failure of these vaccines. By combining advanced biophysical methods (e.g. atomic force spectroscopy), fluorescence and electron microscopy, and synthetic biology, we aim to remove this mystery. Our objectives are:
1) Generate a ""toolbox"" for glycan-binding antibody research: Recombinant antibodies, BCR knock-in mice and defined glycan antigens as purified molecules, on whole bacteria or on virus-like particle will be developed for model antigens: Salmonella Typhimurium O-antigen and the E.coli K100 capsule.
2) Determine the quantitative relationship between glycan antigen sampling into gut-associated lymphoid tissues and particle size, glycan flexibility/structure, digestion resistance and natural IgA binding.
3) Determine how biophysical properties of glycan antigens affect B cell antigen uptake, T cell help and antibody affinity maturation.
4) Combine models of antigen sampling efficiency and anti-glycan antibody affinity maturation to generate a systems-level model of mucosal vaccine efficacy.
This will uncover the fundamental principles governing the induction of high-affinity anti-glycan sIgA, driving urgently required progress in mucosal vaccine design
"
Summary
"Intestinal bacteria have an enormous influence on health, both in the form of major pathogens and as major constituents of the microbiota. We have demonstrated that high-affinity secretory antibodies (sIgA) offer huge potential to protect from infection and to manipulate microbiota composition. However, designing good oral vaccines to induce high-affinity sIgA is a compound problem. Most protective anti-bacterial sIgA targets bacterial glycans, requiring an understanding of inherently difficult glycan biochemistry. We also need to deliver intact antigen via the highly degradative environment of the intestine. Whole-cell inactivated oral vaccines can induce high-affinity sIgA against some glycan structures, but we have an incomplete picture of what determines the success/failure of these vaccines. By combining advanced biophysical methods (e.g. atomic force spectroscopy), fluorescence and electron microscopy, and synthetic biology, we aim to remove this mystery. Our objectives are:
1) Generate a ""toolbox"" for glycan-binding antibody research: Recombinant antibodies, BCR knock-in mice and defined glycan antigens as purified molecules, on whole bacteria or on virus-like particle will be developed for model antigens: Salmonella Typhimurium O-antigen and the E.coli K100 capsule.
2) Determine the quantitative relationship between glycan antigen sampling into gut-associated lymphoid tissues and particle size, glycan flexibility/structure, digestion resistance and natural IgA binding.
3) Determine how biophysical properties of glycan antigens affect B cell antigen uptake, T cell help and antibody affinity maturation.
4) Combine models of antigen sampling efficiency and anti-glycan antibody affinity maturation to generate a systems-level model of mucosal vaccine efficacy.
This will uncover the fundamental principles governing the induction of high-affinity anti-glycan sIgA, driving urgently required progress in mucosal vaccine design
"
Max ERC Funding
1 993 750 €
Duration
Start date: 2020-07-01, End date: 2025-06-30
Project acronym SocialNAc
Project Circuit and synaptic plasticity mechanisms of approach and avoidance social behavior.
Researcher (PI) Camilla BELLONE
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary Social behavior is defined as any modality of communication and interaction between two or more conspecifics. These behaviors, which include affiliative and antagonistic interactions, are exhibited by all sexually reproducing species, they are characterized by high-level complexity of communication through multiple sensory modalities and they are essential for survival. Humans and other animals living in groups continuously experience situations in which they need to select appropriate behavioral responses upon exposure to conspecifics. At the very basis of this social behavior, an individual needs to decide for example whether to approach (positive or appetitive) or avoid (negative or aversive) other individuals. Here, using mice, we will investigate the brain circuits and synaptic mechanisms involved in conspecific approach and avoidance behavior. The Nucleus Accumbens (NAc) is a key region of the mesocorticolimbic circuits for evaluating appetitive and aversive information. Recent studies have revealed the importance of NAc in social behavior, but which neurons within this structure are relevant and how they contribute to conspecific interaction is largely unknown. We hypothesize that different populations of neurons within the NAc orchestrate and integrate different types of socially relevant information to initiate the appropriate behavioral response. Using in vivo and ex vivo recordings and circuit-specific optogenetic manipulations in specific social interaction conditions, we will investigate how the NAc integrates information about conspecifics and how it incorporates learned associations to initiate conspecific approach or avoidance. This study will thus identify and functionally characterize the circuit and synaptic mechanisms controlling socially appetitive and aversive stimuli, and hence pave the way for a causal understanding of the processes underlying disruption of complex social behaviors in psychiatric disorders.
Summary
Social behavior is defined as any modality of communication and interaction between two or more conspecifics. These behaviors, which include affiliative and antagonistic interactions, are exhibited by all sexually reproducing species, they are characterized by high-level complexity of communication through multiple sensory modalities and they are essential for survival. Humans and other animals living in groups continuously experience situations in which they need to select appropriate behavioral responses upon exposure to conspecifics. At the very basis of this social behavior, an individual needs to decide for example whether to approach (positive or appetitive) or avoid (negative or aversive) other individuals. Here, using mice, we will investigate the brain circuits and synaptic mechanisms involved in conspecific approach and avoidance behavior. The Nucleus Accumbens (NAc) is a key region of the mesocorticolimbic circuits for evaluating appetitive and aversive information. Recent studies have revealed the importance of NAc in social behavior, but which neurons within this structure are relevant and how they contribute to conspecific interaction is largely unknown. We hypothesize that different populations of neurons within the NAc orchestrate and integrate different types of socially relevant information to initiate the appropriate behavioral response. Using in vivo and ex vivo recordings and circuit-specific optogenetic manipulations in specific social interaction conditions, we will investigate how the NAc integrates information about conspecifics and how it incorporates learned associations to initiate conspecific approach or avoidance. This study will thus identify and functionally characterize the circuit and synaptic mechanisms controlling socially appetitive and aversive stimuli, and hence pave the way for a causal understanding of the processes underlying disruption of complex social behaviors in psychiatric disorders.
Max ERC Funding
1 996 424 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
