Project acronym SynPlex
Project Tailored chemical complexity through evolution-inspired synthetic biology
Researcher (PI) Joern PIEL
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS9, ERC-2016-ADG
Summary Creating true molecular complexity in a modular, combinatorial fashion is one of the great visions in applied enzymology and chemistry. Nature achieves this feat by using modular biosynthetic enzymes. These microbial proteins generate many of the most important natural products of therapeutic value, including antiinfective, anticancer, and immunosuppressive agents. To construct such compounds, each enzyme module incorporates and often modifies one building block in an assembly line-like process. Among the known modular enzymes, the recently discovered trans-acyltransferase polyketide synthases (trans-AT PKSs) exhibit an unparalleled biosynthetic diversity and tendency to form extensively mosaic-like hybrid enzymes during evolution. As a consequence, many bioactive polyketides generated by these enzymes exhibit combinatorial-like hybrid structures. This phenomenon provides unprecedented opportunities to understand the evolution of metabolic complexity and to apply these principles to metabolic engineering through parts-based synthetic biology. SynPlex will use a novel hypothesis-driven, multi-faceted strategy to interrogate and utilize the distinct combinatorial properties and metabolic richness of trans-AT PKSs. This multidisciplinary project aims to (i) unravel principles of how mosaic PKSs and their metabolites are formed in Nature, (ii) characterize non-canonical PKS components, (iii) create a toolbox of PKS parts for synthetic biology based on these evolutionary and biochemical principles, and (iv) harness the combinatorial potential of trans-AT systems to access complex natural as well as non-natural products. This innovative concept that merges evolutionary biology, enzymology, synthetic biology, and chemistry will result in a broad understanding of these most complex of all known proteins. It has the potential to provide generic, robust synthetic biology platforms to engineer complex polyketides with a wide range of features in a predictable way.
Summary
Creating true molecular complexity in a modular, combinatorial fashion is one of the great visions in applied enzymology and chemistry. Nature achieves this feat by using modular biosynthetic enzymes. These microbial proteins generate many of the most important natural products of therapeutic value, including antiinfective, anticancer, and immunosuppressive agents. To construct such compounds, each enzyme module incorporates and often modifies one building block in an assembly line-like process. Among the known modular enzymes, the recently discovered trans-acyltransferase polyketide synthases (trans-AT PKSs) exhibit an unparalleled biosynthetic diversity and tendency to form extensively mosaic-like hybrid enzymes during evolution. As a consequence, many bioactive polyketides generated by these enzymes exhibit combinatorial-like hybrid structures. This phenomenon provides unprecedented opportunities to understand the evolution of metabolic complexity and to apply these principles to metabolic engineering through parts-based synthetic biology. SynPlex will use a novel hypothesis-driven, multi-faceted strategy to interrogate and utilize the distinct combinatorial properties and metabolic richness of trans-AT PKSs. This multidisciplinary project aims to (i) unravel principles of how mosaic PKSs and their metabolites are formed in Nature, (ii) characterize non-canonical PKS components, (iii) create a toolbox of PKS parts for synthetic biology based on these evolutionary and biochemical principles, and (iv) harness the combinatorial potential of trans-AT systems to access complex natural as well as non-natural products. This innovative concept that merges evolutionary biology, enzymology, synthetic biology, and chemistry will result in a broad understanding of these most complex of all known proteins. It has the potential to provide generic, robust synthetic biology platforms to engineer complex polyketides with a wide range of features in a predictable way.
Max ERC Funding
2 495 755 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym SYNVGLUT
Project Vesicular glutamate transporters as molecular regulators of neural communication
Researcher (PI) Christian Rosenmund
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary This proposal describes experiments aimed at defining the multiple roles of vesicular glutamate transporters (VGLUTs) in central synapses. Classically, VGLUTs transport glutamate from the cytoplasm into synaptic vesicles. Deletion of these genes disrupts synaptic glutamate release and their expression suffices to determine neurons as glutamatergic. We recently discovered that VGLUTs control additional key parameters such as quantal size and vesicular release probability, suggesting that they are fundamental regulators of synaptic strength and synaptic plasticity. To study these novel functions, we will first address whether the number of VGLUTs per vesicle (VGLUT content) can affect the amount of stored glutamate and in addition, the probability of vesicle release. We will subsequently explore the underlying mechanisms. Second, we will test the hypothesis that different VGLUT paralogs contribute to functional differences in discrete synapse populations, as implied by our preliminary data and the distribution pattern of the two main paralogs VGLUT1 and VGLUT2 in the brain. Subsequently, we will perform structure function studies on VGLUTs in native synapses to identify the underlying molecular interactions. Finally, the little understood VGLUT3 paralog is expressed mainly in subclasses of cholinergic, dopaminergic and GABAergic neurons, but no evidence exists that demonstrates VGLUT3 s role in glutamate release. We will address whether VGLUT3 is used to co-release glutamate with other neurotransmitters, and will test whether presence of glutamate in synaptic vesicles interferes with the storage or release of other neurotransmitters. Our studies will yield important insights into how these transporters operate, and how modulation of VGLUTs affects synaptic encoding and brain function. Because of observed profound regulation of VGLUTs in schizophrenia, depression and Parkinsons disease, these findings will also contribute to diagnosis and treatment of mental illness.
Summary
This proposal describes experiments aimed at defining the multiple roles of vesicular glutamate transporters (VGLUTs) in central synapses. Classically, VGLUTs transport glutamate from the cytoplasm into synaptic vesicles. Deletion of these genes disrupts synaptic glutamate release and their expression suffices to determine neurons as glutamatergic. We recently discovered that VGLUTs control additional key parameters such as quantal size and vesicular release probability, suggesting that they are fundamental regulators of synaptic strength and synaptic plasticity. To study these novel functions, we will first address whether the number of VGLUTs per vesicle (VGLUT content) can affect the amount of stored glutamate and in addition, the probability of vesicle release. We will subsequently explore the underlying mechanisms. Second, we will test the hypothesis that different VGLUT paralogs contribute to functional differences in discrete synapse populations, as implied by our preliminary data and the distribution pattern of the two main paralogs VGLUT1 and VGLUT2 in the brain. Subsequently, we will perform structure function studies on VGLUTs in native synapses to identify the underlying molecular interactions. Finally, the little understood VGLUT3 paralog is expressed mainly in subclasses of cholinergic, dopaminergic and GABAergic neurons, but no evidence exists that demonstrates VGLUT3 s role in glutamate release. We will address whether VGLUT3 is used to co-release glutamate with other neurotransmitters, and will test whether presence of glutamate in synaptic vesicles interferes with the storage or release of other neurotransmitters. Our studies will yield important insights into how these transporters operate, and how modulation of VGLUTs affects synaptic encoding and brain function. Because of observed profound regulation of VGLUTs in schizophrenia, depression and Parkinsons disease, these findings will also contribute to diagnosis and treatment of mental illness.
Max ERC Funding
2 413 200 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym TEMUBLYM
Project Teleost mucosal B1-like lymphocytes at the crossroad of tolerance and immunity
Researcher (PI) Carolina TAFALLA PINEIRO
Host Institution (HI) INSTITUTO NACIONAL DE INVESTIGACION Y TECNOLOGIA AGRARIA Y ALIMENTARIA OA MP
Call Details Consolidator Grant (CoG), LS9, ERC-2016-COG
Summary B cells are one of the main players of immunity, responsible for the production of immunoglobulins (Igs). In 2011, I was granted an ERC Starting grant to undertake the phenotypical and functional characterization of teleost B lymphocytes based on the hypothesis that they do not behave as mammalian B2 cells (conventional B cells) but closely resemble mammalian innate B1 lymphocytes involved in extrafollicular T-independent (TI) responses. Since then, my laboratory has gathered considerable evidences that strengthen this hypothesis. These studies were mostly carried out in central lymphoid compartments, but did not address how teleost B1-like cells regulate the delicate balance between immunity and tolerance at mucosal interfaces, in species lacking follicular structures. In this new project, I want to pursue my studies on B lymphocyte functionality, focusing on how teleost mucosal B cells are regulated, still under the assumption that fish B lymphocytes resemble better a B1 model. We will study how fish B cells differentiate to antibody secreting cells (ASCs) and establish extrafollicular long-term memory, taking into account novel results in mammals that have challenged traditional paradigms and revealed that long-term immunological memory can be established through TI IgM B1-like responses. Furthermore, we will also study the role of IgD in the gills, as previous studies from my group suggest that this Ig plays a key role in the regulation of immunity in this specific mucosa, as it seems to do in humans in areas such as the upper respiratory tract.
Addressing how fish B cells mount a protective mucosal immune response in the absence of T cell help from organized follicles could provide new mechanistic insights into IgM and IgD responses emerging in humans. From a practical view, our work will contribute to understand why satisfactory mucosal vaccination is still an unreached goal for most diseases in both mammals and fish, despite their strong demand.
Summary
B cells are one of the main players of immunity, responsible for the production of immunoglobulins (Igs). In 2011, I was granted an ERC Starting grant to undertake the phenotypical and functional characterization of teleost B lymphocytes based on the hypothesis that they do not behave as mammalian B2 cells (conventional B cells) but closely resemble mammalian innate B1 lymphocytes involved in extrafollicular T-independent (TI) responses. Since then, my laboratory has gathered considerable evidences that strengthen this hypothesis. These studies were mostly carried out in central lymphoid compartments, but did not address how teleost B1-like cells regulate the delicate balance between immunity and tolerance at mucosal interfaces, in species lacking follicular structures. In this new project, I want to pursue my studies on B lymphocyte functionality, focusing on how teleost mucosal B cells are regulated, still under the assumption that fish B lymphocytes resemble better a B1 model. We will study how fish B cells differentiate to antibody secreting cells (ASCs) and establish extrafollicular long-term memory, taking into account novel results in mammals that have challenged traditional paradigms and revealed that long-term immunological memory can be established through TI IgM B1-like responses. Furthermore, we will also study the role of IgD in the gills, as previous studies from my group suggest that this Ig plays a key role in the regulation of immunity in this specific mucosa, as it seems to do in humans in areas such as the upper respiratory tract.
Addressing how fish B cells mount a protective mucosal immune response in the absence of T cell help from organized follicles could provide new mechanistic insights into IgM and IgD responses emerging in humans. From a practical view, our work will contribute to understand why satisfactory mucosal vaccination is still an unreached goal for most diseases in both mammals and fish, despite their strong demand.
Max ERC Funding
1 866 046 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym TMIHCV
Project Microfabrication-Based Rational Design of Transcriptional-Metabolic Intervention for the Treatment of Hepatitis C Virus (HCV) Infection
Researcher (PI) Yaakov Nahmias
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Summary
Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Max ERC Funding
1 994 395 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym TREATPD
Project Cell and gene therapy based approaches for treatment of Parkinson's disease: from models to clinics
Researcher (PI) Deniz Kirik
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.
Summary
Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.
Max ERC Funding
1 508 940 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym ventralHippocampus
Project Neuronal circuits for emotions in the ventral CA1 hippocampus
Researcher (PI) Stéphane CIOCCHI
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary A fundamental objective in modern neurosciences is to understand the neural mechanisms of learning and memory in both healthy and pathological conditions. The hippocampus is a high-order cortical brain region important for emotions and cognition. The ventral subdivision of the hippocampus (anterior hippocampus in primates) is mostly involved in anxiety and contextual fear conditioning behaviours.
Pyramidal cells of the CA1 region of the hippocampus represent a main hippocampal output to numerous brains regions relevant for emotional and cognitive processes. The activity and timing of these CA1 pyramidal cells are controlled by a set of very diverse long-range afferent inputs and by local GABAergic interneurons. However, the function of afferent pathways to- and of local GABAergic interneurons in the ventral CA1 hippocampus during contextual fear conditioning and anxiety behaviours have not been investigated so far. We hypothesise that distinct sub-circuits in the ventral CA1 hippocampus differentially contribute to emotional behaviours by diverse and complementary neuronal and network mechanisms.
To test this hypothesis, we will use an innovative cross-level approach combining single-unit recordings of ventral CA1 GABAergic interneurons and of afferent brain regions to the ventral CA1 hippocampus, local field potential recordings, selective optogenetic strategies, cell-type-specific viral tracing, juxtacellular recording and labelling from ventral CA1 GABAergic interneurons, and behavioural paradigms in rodents. The originality of the proposal relies on identifying specific neuronal circuits and mechanisms in the ventral CA1 hippocampus to understand how normal and pathological brain function might arise at the behavioural level. Altogether, my research proposal aims at discovering logics of cortical computations during behaviour which may lead to translational applications for the clinics.
Summary
A fundamental objective in modern neurosciences is to understand the neural mechanisms of learning and memory in both healthy and pathological conditions. The hippocampus is a high-order cortical brain region important for emotions and cognition. The ventral subdivision of the hippocampus (anterior hippocampus in primates) is mostly involved in anxiety and contextual fear conditioning behaviours.
Pyramidal cells of the CA1 region of the hippocampus represent a main hippocampal output to numerous brains regions relevant for emotional and cognitive processes. The activity and timing of these CA1 pyramidal cells are controlled by a set of very diverse long-range afferent inputs and by local GABAergic interneurons. However, the function of afferent pathways to- and of local GABAergic interneurons in the ventral CA1 hippocampus during contextual fear conditioning and anxiety behaviours have not been investigated so far. We hypothesise that distinct sub-circuits in the ventral CA1 hippocampus differentially contribute to emotional behaviours by diverse and complementary neuronal and network mechanisms.
To test this hypothesis, we will use an innovative cross-level approach combining single-unit recordings of ventral CA1 GABAergic interneurons and of afferent brain regions to the ventral CA1 hippocampus, local field potential recordings, selective optogenetic strategies, cell-type-specific viral tracing, juxtacellular recording and labelling from ventral CA1 GABAergic interneurons, and behavioural paradigms in rodents. The originality of the proposal relies on identifying specific neuronal circuits and mechanisms in the ventral CA1 hippocampus to understand how normal and pathological brain function might arise at the behavioural level. Altogether, my research proposal aims at discovering logics of cortical computations during behaviour which may lead to translational applications for the clinics.
Max ERC Funding
1 493 736 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym WOUND CONTRACTION
Project Keratinocytes and Matrix metalloproteinases: driving force of skin wound contraction?
Researcher (PI) Ursula Mirastschijski
Host Institution (HI) UNIVERSITAET BREMEN
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Two unconventional concepts of skin contraction are presented that could change the current paradigm of wound healing. The overall objective is to clarify the underlying processes and to develop new therapies to prevent excessive scarring, ameliorate patients lives and reduce medical health care expenses. Specific emphasis lies on the role of Matrix metalloproteinases (MMP) and keratinocytes. Previous internationally acknowledged work of the PI resulted in these challenging concepts. The project will take place at the Medical School Hannover with its vast scientific infrastructure perfectly suited for this type of pioneer research. Unconventional is the concept that MMP lead to contrary cell responses. By degrading matrix molecules, MMP induce cell disassembly and migration. Only MMP-3 and -7 cleave cadherins and induce adhesion. MMP-3 deficient mice showed normal wound epithelialisation without contraction. Presumably by controlled proteolysis of intercellular molecules, cell adhesivity increases. Firm adhesion complexes provide stable anchorage sites for force generation. Selective MMP-3 inhibition would reduce contraction without impairing epithelialisation. The concept of the epithelial role in contraction differs from the paradigm and marks a beyond the state-of-art approach in wound healing. Keratinocytes at the air-liquid interphase close wounds by reepithelialisation and surface minimization. Hence, reduction of surface tension would decrease epidermal contraction. Alveolar surface tension is reduced by surfactants in preterm infants. Assuming that epidermal wounds could profit of surfactants is a high risk high gain approach of tackling hypertrophic scarring, but if successful it would revolutionize burn wound therapy.
Summary
Two unconventional concepts of skin contraction are presented that could change the current paradigm of wound healing. The overall objective is to clarify the underlying processes and to develop new therapies to prevent excessive scarring, ameliorate patients lives and reduce medical health care expenses. Specific emphasis lies on the role of Matrix metalloproteinases (MMP) and keratinocytes. Previous internationally acknowledged work of the PI resulted in these challenging concepts. The project will take place at the Medical School Hannover with its vast scientific infrastructure perfectly suited for this type of pioneer research. Unconventional is the concept that MMP lead to contrary cell responses. By degrading matrix molecules, MMP induce cell disassembly and migration. Only MMP-3 and -7 cleave cadherins and induce adhesion. MMP-3 deficient mice showed normal wound epithelialisation without contraction. Presumably by controlled proteolysis of intercellular molecules, cell adhesivity increases. Firm adhesion complexes provide stable anchorage sites for force generation. Selective MMP-3 inhibition would reduce contraction without impairing epithelialisation. The concept of the epithelial role in contraction differs from the paradigm and marks a beyond the state-of-art approach in wound healing. Keratinocytes at the air-liquid interphase close wounds by reepithelialisation and surface minimization. Hence, reduction of surface tension would decrease epidermal contraction. Alveolar surface tension is reduced by surfactants in preterm infants. Assuming that epidermal wounds could profit of surfactants is a high risk high gain approach of tackling hypertrophic scarring, but if successful it would revolutionize burn wound therapy.
Max ERC Funding
1 299 840 €
Duration
Start date: 2009-12-01, End date: 2015-11-30
Project acronym ZEBRAFISH PERCEPTION
Project Sensory perception: neural representation and modulation
Researcher (PI) German Sumbre
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Perception has intrigued philosophers and scientists since Aristotle ~2,300 years ago, but only recently it became technically possible to address its underlying neural mechanisms. The main scientific research approach still focuses on studying the evoked responses to a perceived sensory stimulus. However, in a state of sensory deprivation, sensory areas in the brain remain highly active. This activity, once interpreted as irrelevant noise, has been found to exhibit highly coherent spatiotemporal structures, suggesting a possible role in perception. Here, I propose to test the hypothesis that perception results as a consequence of the interaction between the dynamic internal state of the brain and the activity evoked by sensory experience. For this purpose, I shall use the zebrafish larva as the experimental model, and a multidisciplinary approach involving two-photon imaging of neural network activities with single cell resolution, behavioural assays, novel mathematical methods for data analysis and genetic engineering techniques to label and manipulate activity of specific cell types or entire networks. The zebrafish model offers the advantage of combining simultaneously all these techniques in an intact behaving vertebrate. I shall specifically examine: 1) The Neuronal representation of sensory perception 2) The role of ongoing spontaneous activity in sensory perception 3) The effect of sensory experience on perception The proposed multidisciplinary approach will shed new light on how information flows through the nervous system; how sensory stimuli are detected, processed and converted into motor behaviours. The findings of this project should provide clear hypotheses regarding analogous and poorly-understood processes in mammals. The work could therefore contribute to understanding of neurological disorders, such as tinnitus, phantom limb and other hallucinations, in which sensory experience is perceived in the absence of external stimulation.
Summary
Perception has intrigued philosophers and scientists since Aristotle ~2,300 years ago, but only recently it became technically possible to address its underlying neural mechanisms. The main scientific research approach still focuses on studying the evoked responses to a perceived sensory stimulus. However, in a state of sensory deprivation, sensory areas in the brain remain highly active. This activity, once interpreted as irrelevant noise, has been found to exhibit highly coherent spatiotemporal structures, suggesting a possible role in perception. Here, I propose to test the hypothesis that perception results as a consequence of the interaction between the dynamic internal state of the brain and the activity evoked by sensory experience. For this purpose, I shall use the zebrafish larva as the experimental model, and a multidisciplinary approach involving two-photon imaging of neural network activities with single cell resolution, behavioural assays, novel mathematical methods for data analysis and genetic engineering techniques to label and manipulate activity of specific cell types or entire networks. The zebrafish model offers the advantage of combining simultaneously all these techniques in an intact behaving vertebrate. I shall specifically examine: 1) The Neuronal representation of sensory perception 2) The role of ongoing spontaneous activity in sensory perception 3) The effect of sensory experience on perception The proposed multidisciplinary approach will shed new light on how information flows through the nervous system; how sensory stimuli are detected, processed and converted into motor behaviours. The findings of this project should provide clear hypotheses regarding analogous and poorly-understood processes in mammals. The work could therefore contribute to understanding of neurological disorders, such as tinnitus, phantom limb and other hallucinations, in which sensory experience is perceived in the absence of external stimulation.
Max ERC Funding
1 851 600 €
Duration
Start date: 2009-11-01, End date: 2015-09-30
