Project acronym 2STEPPARKIN
Project A novel two-step model for neurodegeneration in Parkinson’s disease
Researcher (PI) Emi Nagoshi
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.
Max ERC Funding
1 518 960 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym Amygdala Circuits
Project Amygdala Circuits for Appetitive Conditioning
Researcher (PI) Andreas Luthi
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Summary
The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.
Max ERC Funding
2 497 200 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym astromnesis
Project The language of astrocytes: multilevel analysis to understand astrocyte communication and its role in memory-related brain operations and in cognitive behavior
Researcher (PI) Andrea Volterra
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.
Summary
In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.
Max ERC Funding
2 513 896 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym AXPLAST
Project Deep brain imaging of cellular mechanisms of sensory processing and learning
Researcher (PI) Jan GRUNDEMANN
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Summary
Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Max ERC Funding
1 475 475 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BRAINCOMPATH
Project Mesoscale Brain Dynamics: Computing with Neuronal Pathways
Researcher (PI) Fritjof Helmchen
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS5, ERC-2014-ADG
Summary Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Summary
Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.
Max ERC Funding
2 498 915 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym CELLTYPESANDCIRCUITS
Project Neural circuit function in the retina of mice and humans
Researcher (PI) Botond Roska
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (multitasking cell types), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform a single computation or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.
Summary
The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (multitasking cell types), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform a single computation or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.
Max ERC Funding
1 499 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym CERDEV
Project Transcriptional controls over cerebellar neuron differentiation and circuit assembly
Researcher (PI) Ludovic TELLEY
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Summary
The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Max ERC Funding
1 499 885 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym COMPUSLANG
Project Neural and computational determinants of left cerebral dominance in speech and language
Researcher (PI) Anne-Lise Mamessier
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary More than a century after Wernicke and Broca established that speech perception and production rely on temporal and prefrontal cortices of the left brain hemisphere, the biological determinants for this organization are still unknown. While functional neuroanatomy has been described in great detail, the neuroscience of language still lacks a physiologically plausible model of the neuro-computational mechanisms for coding and decoding of speech acoustic signal. We propose to fill this gap by testing the biological validity and exploring the computational implications of one promising proposal, the Asymmetric Sampling in Time theory. AST assumes that speech signals are analysed in parallel at multiple timescales and that these timescales differ between left and right cerebral hemispheres. This theory is original and provocative as it implies that a single computational difference, distinct integration windows in right and left auditory cortices could be sufficient to explain why speech is preferentially processed by the left brain, and possible even why the human brain has evolved toward such an asymmetric functional organization. Our proposal has four goals: 1/ to validate, invalidate or amend AST on the basis of physiological experiments in healthy human subjects including functional magnetic resonance imaging (fMRI), combined electroencephalography (EEG) and fMRI, magnetoencephalography (MEG) and subdural electrocorticography (EcoG), 2/ to use computational modeling to probe those aspects of the theory that currently remain inaccessible to empirical testing (evaluation, assessment), 3/ to apply AST to binaural artificial hearing with cochlear implants, 4/ to test for disorders of auditory sampling in autism and dyslexia, two language neurodevelopmental pathologies in which a genetic basis implicates the physiological underpinnings of AST, and 5/ to assess potential generalisation of AST to linguistic action in the context of speech production.
Summary
More than a century after Wernicke and Broca established that speech perception and production rely on temporal and prefrontal cortices of the left brain hemisphere, the biological determinants for this organization are still unknown. While functional neuroanatomy has been described in great detail, the neuroscience of language still lacks a physiologically plausible model of the neuro-computational mechanisms for coding and decoding of speech acoustic signal. We propose to fill this gap by testing the biological validity and exploring the computational implications of one promising proposal, the Asymmetric Sampling in Time theory. AST assumes that speech signals are analysed in parallel at multiple timescales and that these timescales differ between left and right cerebral hemispheres. This theory is original and provocative as it implies that a single computational difference, distinct integration windows in right and left auditory cortices could be sufficient to explain why speech is preferentially processed by the left brain, and possible even why the human brain has evolved toward such an asymmetric functional organization. Our proposal has four goals: 1/ to validate, invalidate or amend AST on the basis of physiological experiments in healthy human subjects including functional magnetic resonance imaging (fMRI), combined electroencephalography (EEG) and fMRI, magnetoencephalography (MEG) and subdural electrocorticography (EcoG), 2/ to use computational modeling to probe those aspects of the theory that currently remain inaccessible to empirical testing (evaluation, assessment), 3/ to apply AST to binaural artificial hearing with cochlear implants, 4/ to test for disorders of auditory sampling in autism and dyslexia, two language neurodevelopmental pathologies in which a genetic basis implicates the physiological underpinnings of AST, and 5/ to assess potential generalisation of AST to linguistic action in the context of speech production.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym ConCorND
Project Connectivity Correlate of Molecular Pathology in Neurodegeneration
Researcher (PI) Smita SAXENA
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Summary
Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym CorPain
Project Dissection of a cortical microcircuit for the processing of pain affect
Researcher (PI) Thomas Nevian
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary It is a fundamental but still elusive question how nociceptive processing is performed in neuronal networks in the cortex for the conscious experience of pain.
The objective of this project is to identify and characterize the cortical microcircuits in the anterior cingulate cortex (ACC) that are involved in pain processing with cellular resolution. The ACC is essential for evaluating the emotional/affective component of pain. Our research will investigate the elusive question if a dedicated pain circuit exists in the ACC. We will dissect the detailed structure and connectivity of this pain circuit and investigate how it generates affective behavioural responses related to pain.
At the core of this project, we will characterize the neuronal networks in the ACC that are engaged in the processing of noxious stimuli. It will be highly interesting to determine the neuronal dynamics in the ACC during nociception and in chronic pain conditions on the cellular and network level. Furthermore, we will elucidate the downstream targets that are influenced by the pain circuits in the ACC to generate the appropriate behavioural responses.
These aims will be achieved by a combination of electrophysiology, 2-photon Ca2+ imaging and pharmaco- and opto-genetic approaches both in vivo and in vitro and behavioural testing of pain affect in mice.
This project will give a comprehensive picture of how a cortical microcircuit processes afferent noxious stimuli to generate an affective behavioural response. This study will give important insight into the fundamental question of cortical information processing and it is highly relevant to understand pain processing and the changes in the network dynamics that manifest the transition to chronic pain. Eventually this might contribute to the development of novel treatment strategies for this pathological condition.
Summary
It is a fundamental but still elusive question how nociceptive processing is performed in neuronal networks in the cortex for the conscious experience of pain.
The objective of this project is to identify and characterize the cortical microcircuits in the anterior cingulate cortex (ACC) that are involved in pain processing with cellular resolution. The ACC is essential for evaluating the emotional/affective component of pain. Our research will investigate the elusive question if a dedicated pain circuit exists in the ACC. We will dissect the detailed structure and connectivity of this pain circuit and investigate how it generates affective behavioural responses related to pain.
At the core of this project, we will characterize the neuronal networks in the ACC that are engaged in the processing of noxious stimuli. It will be highly interesting to determine the neuronal dynamics in the ACC during nociception and in chronic pain conditions on the cellular and network level. Furthermore, we will elucidate the downstream targets that are influenced by the pain circuits in the ACC to generate the appropriate behavioural responses.
These aims will be achieved by a combination of electrophysiology, 2-photon Ca2+ imaging and pharmaco- and opto-genetic approaches both in vivo and in vitro and behavioural testing of pain affect in mice.
This project will give a comprehensive picture of how a cortical microcircuit processes afferent noxious stimuli to generate an affective behavioural response. This study will give important insight into the fundamental question of cortical information processing and it is highly relevant to understand pain processing and the changes in the network dynamics that manifest the transition to chronic pain. Eventually this might contribute to the development of novel treatment strategies for this pathological condition.
Max ERC Funding
1 928 125 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
