Project acronym 5HT-OPTOGENETICS
Project Optogenetic Analysis of Serotonin Function in the Mammalian Brain
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Summary
Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Max ERC Funding
2 318 636 €
Duration
Start date: 2010-07-01, End date: 2015-12-31
Project acronym ACTIVE_NEUROGENESIS
Project Activity-dependent signaling in radial glial cells and their neuronal progeny
Researcher (PI) Colin Akerman
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.
Summary
A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.
Max ERC Funding
1 284 808 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym BRAINCANNABINOIDS
Project Understanding the molecular blueprint and functional complexity of the endocannabinoid metabolome in the brain
Researcher (PI) István Katona
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Summary
We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Max ERC Funding
1 638 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym BRAINPOWER
Project Brain energy supply and the consequences of its failure
Researcher (PI) David Ian Attwell
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Summary
Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Max ERC Funding
2 499 947 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym COGSYSTEMS
Project Understanding actions and intentions of others
Researcher (PI) Giacomo Rizzolatti
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PARMA
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.
Summary
How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.
Max ERC Funding
1 992 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym DENDRITE
Project Cellular and circuit determinants of dendritic computation
Researcher (PI) Michael Andreas Hausser
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.
Summary
What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.
Max ERC Funding
2 416 078 €
Duration
Start date: 2010-06-01, End date: 2016-05-31
Project acronym DHISP
Project Dorsal Horn Interneurons in Sensory Processing
Researcher (PI) Hanns Ulrich Zeilhofer
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Chronic pain syndromes are to a large extent due to maladaptive plastic changes in the CNS. A CNS area particularly relevant for such changes is the spinal dorsal horn, where inputs from nociceptive and non-nociceptive fibers undergo their first synaptic integration. This area harbors a sophisticated network of interneurons, which function as a gate-control unit for incoming sensory signals. Several different types of interneurons can be distinguished based e.g. on their neurotransmitter and neuropeptide content. Despite more than 40 years of research, our knowledge about the integration of these neurons in dorsal horn circuits and their contribution to sensory processing is still very limited. This proposal aims at a comprehensive characterization of the dorsal horn neuronal network under normal conditions and in chronic pain states with a focus on inhibitory interneurons. A genome-wide analysis of the gene expression profile shall be made from defined dorsal horn interneurons genetically tagged with fluorescent markers and isolated by fluorescence activated cell sorting. A functional characterization of the connectivity of these neurons in spinal cord slices and of their role in in vivo sensory processing shall be achieved with optogenetic tools (channelrhodopsin-2), which permit activation of these neurons with light. Finally, behavioral analyses shall be made in mice after diphteria toxin-mediated ablation of defined interneuron types. All three approaches shall be applied to naïve mice and to mice with inflammatory or neuropathic pain. The results from these studies will improve our understanding of the malfunctioning of sensory processing in chronic pain states and will provide the basis for novel approaches to the prevention or reversal of chronic pain states.
Summary
Chronic pain syndromes are to a large extent due to maladaptive plastic changes in the CNS. A CNS area particularly relevant for such changes is the spinal dorsal horn, where inputs from nociceptive and non-nociceptive fibers undergo their first synaptic integration. This area harbors a sophisticated network of interneurons, which function as a gate-control unit for incoming sensory signals. Several different types of interneurons can be distinguished based e.g. on their neurotransmitter and neuropeptide content. Despite more than 40 years of research, our knowledge about the integration of these neurons in dorsal horn circuits and their contribution to sensory processing is still very limited. This proposal aims at a comprehensive characterization of the dorsal horn neuronal network under normal conditions and in chronic pain states with a focus on inhibitory interneurons. A genome-wide analysis of the gene expression profile shall be made from defined dorsal horn interneurons genetically tagged with fluorescent markers and isolated by fluorescence activated cell sorting. A functional characterization of the connectivity of these neurons in spinal cord slices and of their role in in vivo sensory processing shall be achieved with optogenetic tools (channelrhodopsin-2), which permit activation of these neurons with light. Finally, behavioral analyses shall be made in mice after diphteria toxin-mediated ablation of defined interneuron types. All three approaches shall be applied to naïve mice and to mice with inflammatory or neuropathic pain. The results from these studies will improve our understanding of the malfunctioning of sensory processing in chronic pain states and will provide the basis for novel approaches to the prevention or reversal of chronic pain states.
Max ERC Funding
2 467 000 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym FRONTEX
Project Decision-making and prefrontal executive function
Researcher (PI) Etienne Koechlin
Host Institution (HI) ECOLE NORMALE SUPERIEURE
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary The prefrontal cortex (PFC) subserves decision-making and executive control, i.e. the ability to make decisions and to regulate behavior according to external events, mental models of situations, internal drives and subjective preferences. Our overall aim is to understand the functional architecture of the human PFC and computational mechanisms of PFC function. The PFC function is known to operate along three major dimensions, namely the affective, motivational and cognitive control of action subserved by the orbital, medial and lateral sectors of the PFC, respectively. In this project, our specific objectives are to solve the following three open issues of critical theoretical significance: (1) the functional organization of motivational control in the medial prefrontal cortex; (2) the mechanisms that enables the PFC to control the learning of representational sets required for cognitive control; (3) the functional interactions between the medial and lateral prefrontal cortex, i.e. the integration of motivational and cognitive control into a unitary decision-making and control system. We will address these theoretically and methodologically challenging issues by elaborating computational models that integrate learning and control mechanisms, and in relation to these models, by conducting functional magnetic resonance imaging experiments in healthy humans. The project is expected to significantly improve our knowledge of the human PFC function. This basic project has potential major implications especially in medicine, because alterations of the prefrontal function is observed in aging and most neuropsychiatric diseases, as well as in technology for developing artificial and robotics intelligence with human-like adaptive reasoning and decision-making abilities.
Summary
The prefrontal cortex (PFC) subserves decision-making and executive control, i.e. the ability to make decisions and to regulate behavior according to external events, mental models of situations, internal drives and subjective preferences. Our overall aim is to understand the functional architecture of the human PFC and computational mechanisms of PFC function. The PFC function is known to operate along three major dimensions, namely the affective, motivational and cognitive control of action subserved by the orbital, medial and lateral sectors of the PFC, respectively. In this project, our specific objectives are to solve the following three open issues of critical theoretical significance: (1) the functional organization of motivational control in the medial prefrontal cortex; (2) the mechanisms that enables the PFC to control the learning of representational sets required for cognitive control; (3) the functional interactions between the medial and lateral prefrontal cortex, i.e. the integration of motivational and cognitive control into a unitary decision-making and control system. We will address these theoretically and methodologically challenging issues by elaborating computational models that integrate learning and control mechanisms, and in relation to these models, by conducting functional magnetic resonance imaging experiments in healthy humans. The project is expected to significantly improve our knowledge of the human PFC function. This basic project has potential major implications especially in medicine, because alterations of the prefrontal function is observed in aging and most neuropsychiatric diseases, as well as in technology for developing artificial and robotics intelligence with human-like adaptive reasoning and decision-making abilities.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym GABA NETWORKS
Project Maturation of functional cortical GABAergic microcircuits
Researcher (PI) Rosa Cossart
Host Institution (HI) UNIVERSITE D'AIX MARSEILLE
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Cortical network function is strongly modulated by the action of GABA interneurons. Understanding the role of different types of interneurons in the generation of network patterns is thus essential. Developmental neurobiology offers both conceptual and experimental tools to address this question. Our research is centred on the integration of GABAergic microcircuits into a functional network during brain development. To describe cortical networks at the scale of microcircuits, we have developed a multidisciplinary approach that combines fast imaging of network dynamics, online data analysis, targeted electrophysiological recordings and histology (Cossart et al. 2005). Doing so, we found a major general step in the maturation of cortical networks. The first electrical network pattern, SPA (Synchronous Plateau Assemblies) emerges at birth and synchronizes electrically coupled neuronal assemblies (Crépel et al., 2007, Allene et al. 2008). We propose that SPAs are a critical step in the maturation of GABAergic microcircuits. More recently, we showed that developing hippocampal networks follow a scale-free topology and demonstrated the existence of functional hubs driving early network oscillations (Bonifazi et al. 2008). These cells are GABAergic neurons characterized by widespread axonal projections. These two findings provide the experimental foundation and conceptual framework for this project. We will address three objectives. First, we will perform a functional characterization of hub neurons orchestrating synchrony in developing cortical networks in vitro and in vivo. Second, we will address the role of SPA in the maturation GABAergic microcircuits. Last, we will examine circuit disorders related to developmental GABA Interneuropathies .
Summary
Cortical network function is strongly modulated by the action of GABA interneurons. Understanding the role of different types of interneurons in the generation of network patterns is thus essential. Developmental neurobiology offers both conceptual and experimental tools to address this question. Our research is centred on the integration of GABAergic microcircuits into a functional network during brain development. To describe cortical networks at the scale of microcircuits, we have developed a multidisciplinary approach that combines fast imaging of network dynamics, online data analysis, targeted electrophysiological recordings and histology (Cossart et al. 2005). Doing so, we found a major general step in the maturation of cortical networks. The first electrical network pattern, SPA (Synchronous Plateau Assemblies) emerges at birth and synchronizes electrically coupled neuronal assemblies (Crépel et al., 2007, Allene et al. 2008). We propose that SPAs are a critical step in the maturation of GABAergic microcircuits. More recently, we showed that developing hippocampal networks follow a scale-free topology and demonstrated the existence of functional hubs driving early network oscillations (Bonifazi et al. 2008). These cells are GABAergic neurons characterized by widespread axonal projections. These two findings provide the experimental foundation and conceptual framework for this project. We will address three objectives. First, we will perform a functional characterization of hub neurons orchestrating synchrony in developing cortical networks in vitro and in vivo. Second, we will address the role of SPA in the maturation GABAergic microcircuits. Last, we will examine circuit disorders related to developmental GABA Interneuropathies .
Max ERC Funding
1 591 300 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym GABACELLSANDMEMORY
Project Linking GABAergic neurones to hippocampal-entorhinal system functions
Researcher (PI) Hannelore Monyer
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary GABAergic interneurones can effectively synchronize the activity of principal cells giving rise to distinct oscillatory patterns. A particular rhythm, hippocampal theta oscillations (6-10Hz), links two ways of coding by which pyramidal cells in the hippocampus represent space, namely rate and phase coding. Thus, the theta cycle provides a clock against which the increased firing rate of pyramidal cells in the hippocampus and entorhinal cortex is measured. Furthermore, hippocampal theta is believed to constitute a link to episodic memory. Recent evidence from our lab indicates that recruitment of GABAergic interneurones critically affects certain aspects of hippocampus-dependent spatial memory in mice. We have established genetic tools that allow us to manipulate GABAergic interneurones in a cell type and region-specific manner. In combination with in vivo electrophysiology in the hippocampus/entorhinal cortex and behavioural studies, we will investigate how GABAergic interneurones regulate the activity in neuronal networks and contribute to behaviour. Specifically, we will address the following questions: 1) How does reduced recruitment of GABAergic interneurones affect network activity (theta oscillations)? 2) How does altered activity of GABAergic interneurones affect spatial representation (activity of place cells in the hippocampus and grid cells in the entorhinal cortex)? 3) How does modified activity in the hippocampus affect activity in the entorhinal cortex (and vice versa)? 4) How does modified network activity and spatial representation translate into spatial memory? The interdisciplinary approach will enable us to provide better insight into how cellular activity of GABAergic interneurones relates to network activity and ultimately to behaviour.
Summary
GABAergic interneurones can effectively synchronize the activity of principal cells giving rise to distinct oscillatory patterns. A particular rhythm, hippocampal theta oscillations (6-10Hz), links two ways of coding by which pyramidal cells in the hippocampus represent space, namely rate and phase coding. Thus, the theta cycle provides a clock against which the increased firing rate of pyramidal cells in the hippocampus and entorhinal cortex is measured. Furthermore, hippocampal theta is believed to constitute a link to episodic memory. Recent evidence from our lab indicates that recruitment of GABAergic interneurones critically affects certain aspects of hippocampus-dependent spatial memory in mice. We have established genetic tools that allow us to manipulate GABAergic interneurones in a cell type and region-specific manner. In combination with in vivo electrophysiology in the hippocampus/entorhinal cortex and behavioural studies, we will investigate how GABAergic interneurones regulate the activity in neuronal networks and contribute to behaviour. Specifically, we will address the following questions: 1) How does reduced recruitment of GABAergic interneurones affect network activity (theta oscillations)? 2) How does altered activity of GABAergic interneurones affect spatial representation (activity of place cells in the hippocampus and grid cells in the entorhinal cortex)? 3) How does modified activity in the hippocampus affect activity in the entorhinal cortex (and vice versa)? 4) How does modified network activity and spatial representation translate into spatial memory? The interdisciplinary approach will enable us to provide better insight into how cellular activity of GABAergic interneurones relates to network activity and ultimately to behaviour.
Max ERC Funding
1 872 000 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
