Project acronym MOLECMAP
Project Quantitative Molecular Map of the Neuronal Surface
Researcher (PI) Zoltan Jozsef Nusser
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Summary
The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
Max ERC Funding
2 494 446 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym PreLog
Project Precursors of logical reasoning in human infants
Researcher (PI) Erno Teglas
Host Institution (HI) KOZEP-EUROPAI EGYETEM
Call Details Starting Grant (StG), SH4, ERC-2014-STG
Summary There is no other field that is more controversial in psychology than that of human reasoning. This project advances a novel theoretical framework focused on the nature and the origins of rationality and could potentially resolve some of these controversies. Theories targeting the mechanisms that allow rational inferences have defined rationality as a function of how much reasoning adheres to formal rules of probability calculus and logic. Classical research with adults and older children collected a large amount of data both in favor and against human rationality, suggesting that reasoning abilities follow a slow maturation. Recent findings on infants’ probabilistic reasoning, including my own earlier research, however, do not support this view. Already preverbal infants seem to form expectations about probabilistic events in accordance with Bayesian rules of inference (Téglás et al, 2011). Here I argue for a similar paradigm change in a related domain, that of deductive reasoning.
In contrast to earlier accounts, I propose that even preverbal infants may possess a core set of logical operations that empower them with sophisticated inferential abilities. First, I focus on the representational precursors of this competence. I argue that infants recruit specific abilities to exploit the conceptual structure of specific event categories that enable them to form logical representations. Thus, information could be stored in a format that can potentially serve as input for subsequent inferences. Further, I will investigate infants’ core logical operations and test how they integrate multiple steps of inferences. This system - indispensable for integrating different bits of knowledge - helps infants to discover information that was not actually present in the input. Such investigations, informed also by adequate neuropsychological evidence would thus contribute to understand the unique nature of human rationality.
Summary
There is no other field that is more controversial in psychology than that of human reasoning. This project advances a novel theoretical framework focused on the nature and the origins of rationality and could potentially resolve some of these controversies. Theories targeting the mechanisms that allow rational inferences have defined rationality as a function of how much reasoning adheres to formal rules of probability calculus and logic. Classical research with adults and older children collected a large amount of data both in favor and against human rationality, suggesting that reasoning abilities follow a slow maturation. Recent findings on infants’ probabilistic reasoning, including my own earlier research, however, do not support this view. Already preverbal infants seem to form expectations about probabilistic events in accordance with Bayesian rules of inference (Téglás et al, 2011). Here I argue for a similar paradigm change in a related domain, that of deductive reasoning.
In contrast to earlier accounts, I propose that even preverbal infants may possess a core set of logical operations that empower them with sophisticated inferential abilities. First, I focus on the representational precursors of this competence. I argue that infants recruit specific abilities to exploit the conceptual structure of specific event categories that enable them to form logical representations. Thus, information could be stored in a format that can potentially serve as input for subsequent inferences. Further, I will investigate infants’ core logical operations and test how they integrate multiple steps of inferences. This system - indispensable for integrating different bits of knowledge - helps infants to discover information that was not actually present in the input. Such investigations, informed also by adequate neuropsychological evidence would thus contribute to understand the unique nature of human rationality.
Max ERC Funding
1 498 137 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym REPCOLLAB
Project Representational preconditions for understanding other minds in the service of human collaboration and social learning
Researcher (PI) Agnes Melinda Kovacs
Host Institution (HI) KOZEP-EUROPAI EGYETEM
Call Details Starting Grant (StG), SH4, ERC-2011-StG_20101124
Summary The central aim of the proposed research project is to systematically explore the empirical implications of a novel theoretical approach to the early representational preconditions and the functional structure of the mechanisms dedicated for understanding other minds. We aim to explore and shed new theoretical light on the basic cognitive and brain mechanisms of the human social mind. One of these mechanisms that has received much attention by earlier approaches to ‘theory-of-mind’ research concerns the ability to infer and represent the mental states of others. Standard theories and research in the last twenty five years have suggested that representing other’s beliefs is an effortful and late developing capacity (Wellman et al., 2001) whose main function is to explain others’ behavior. Here we advance and propose to explore a new theoretical perspective according to which the mechanisms of mental state monitoring and representation involve primarily automatic and effortless processes grounded in on-line cooperative social interactions. Our approach is part of an on-going paradigm change in the field of theory-of-mind research motivated by the recent evidence showing that infants in their second year understand mental states (Onishi & Baillargeon, 2005). Our own research has gone a significant step further by demonstrating that these mechanisms are present as early as 7 month of age, and by showing that both young infants and adults seem to automatically compute others’ beliefs even in situations where they are not required to do so (Kovács et al., 2010). The present project explores the functional sub-components and triggering conditions of young infants’ powerful belief computation abilities and to chart their developmental unfolding. Furthermore, we shall explore the implications of the new theoretical proposal that this dedicated system presupposes as its proper domain the on-going collaborative and communicative interactions.
Summary
The central aim of the proposed research project is to systematically explore the empirical implications of a novel theoretical approach to the early representational preconditions and the functional structure of the mechanisms dedicated for understanding other minds. We aim to explore and shed new theoretical light on the basic cognitive and brain mechanisms of the human social mind. One of these mechanisms that has received much attention by earlier approaches to ‘theory-of-mind’ research concerns the ability to infer and represent the mental states of others. Standard theories and research in the last twenty five years have suggested that representing other’s beliefs is an effortful and late developing capacity (Wellman et al., 2001) whose main function is to explain others’ behavior. Here we advance and propose to explore a new theoretical perspective according to which the mechanisms of mental state monitoring and representation involve primarily automatic and effortless processes grounded in on-line cooperative social interactions. Our approach is part of an on-going paradigm change in the field of theory-of-mind research motivated by the recent evidence showing that infants in their second year understand mental states (Onishi & Baillargeon, 2005). Our own research has gone a significant step further by demonstrating that these mechanisms are present as early as 7 month of age, and by showing that both young infants and adults seem to automatically compute others’ beliefs even in situations where they are not required to do so (Kovács et al., 2010). The present project explores the functional sub-components and triggering conditions of young infants’ powerful belief computation abilities and to chart their developmental unfolding. Furthermore, we shall explore the implications of the new theoretical proposal that this dedicated system presupposes as its proper domain the on-going collaborative and communicative interactions.
Max ERC Funding
1 449 836 €
Duration
Start date: 2012-03-01, End date: 2018-08-31
Project acronym resistance evolution
Project Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Summary
Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Max ERC Funding
1 846 250 €
Duration
Start date: 2015-10-01, End date: 2021-09-30
Project acronym SERRACO
Project Modulation of cortical activity by median raphe neuronal assemblies with identified behavioural effects
Researcher (PI) Tamás Freund
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Summary
Cortical operations are built up from states associated with distinct behaviour-dependent network activity patterns that subserve information aquisition, encoding, memory consolidation and retrieval. Thus, they can be considered as manifestations of different processing modes. Groups of modulatory, largely monoaminergic neurons located in subcortical nuclei innervating all forebrain areas are indispensable for the generation, stabilization and termination of cortical activity states. In recent years the concept of subcortical modulation has been expanded by the discovery of a fast type of modulatory action driving the rapid readjustment of cortical activity and associated behaviours. Thus, cortical networks are under the influence of a tonic, slow, as well as a phasic, rapid component of subcortical modulation that are acting in parallel. Results from our laboratory revealed that the median raphe (MR) nucleus, one of the main sources of serotonergic innervation of the limbic system , besides the non-synaptic diffuse action, also exerts a fast type of modulation via the selective innervation of cortical GABAergic interneurons. This selective effect on local inhibition may be ideal for the synchronous resetting of the target principal cell circuits, or for the continuous tuning of their activity. These discoveries, together with the methodological advances of recent years, enable us to map the neuronal network mechanisms behind transitions of brain states, as well as associated behaviours, induced by subcortical inputs. We will focus on the MR – limbic connection with the aim to unravel the physiological, pharmacological and anatomical features of MR neuronal assemblies, both the slow- and fast-acting, as well as the serotonergic and glutamatergic components (together with their cortical target circuits) that will have been shown - using optic stimulation of ChR2/eGFP virus-infected MR neurons - to evoke characteristic behaviours, such as anxiety and conditioned fear.
Max ERC Funding
2 700 000 €
Duration
Start date: 2012-03-01, End date: 2017-02-28