Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Summary
Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Max ERC Funding
2 489 643 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym CIRCUIT
Project Neural circuits for space representation in the mammalian cortex
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Summary
Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.
Max ERC Funding
2 499 112 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CORTEX
Project Computations by Neurons and Populations in Visual Cortex
Researcher (PI) Matteo Carandini
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Neurons in primary visual cortex (area V1) receive feedforward inputs from thalamic afferents and lateral inputs from other cortical neurons. Little is known about how these components interact to determine the responses of a V1 neuron. One camp ascribes most responses to feedforward mechanisms. The other camp ascribes them mostly to lateral interactions. We propose that these two apparently opposed views can be simply reconciled in a single framework. We hypothesize that area V1 can operate both in a feedforward regime and in a lateral interaction regime, depending on the nature of the stimulus and on the cognitive task at hand, and that the transition from one regime to the other is governed by synaptic inhibition. We will test these hypotheses by recording from individual V1 neurons while monitoring the activity of nearby populations of cortical neurons via multiprobe electrodes. In Aim 1 we will relate the activity of V1 neurons to that of nearby populations. We will use simple measures of correlation and nonlinear models that predict individual spikes to measure how responses depend on a feedforward contribution (the receptive field ) and on a lateral contribution (the connection field ). We will test our first hypothesis, concerning the role of the stimulus in changing this dependence. In Aim 2 we will extend these results to a behaving animal. We will record from V1 of mice performing a 2-alternative forced-choice psychophysical task, and we will test our second hypothesis, concerning the role of the cognitive task in determining the operating regime of the cortex. In Aim 3 we will seek a biophysical interpretation of the functional mechanisms and effective connectivity revealed by the previous Aims. We will test our third hypothesis, concerning the role of synaptic inhibition. The tools involved will include intracellular recordings and optical stimulation in transgenic mice whose cortical neurons are sensitive to light.
Summary
Neurons in primary visual cortex (area V1) receive feedforward inputs from thalamic afferents and lateral inputs from other cortical neurons. Little is known about how these components interact to determine the responses of a V1 neuron. One camp ascribes most responses to feedforward mechanisms. The other camp ascribes them mostly to lateral interactions. We propose that these two apparently opposed views can be simply reconciled in a single framework. We hypothesize that area V1 can operate both in a feedforward regime and in a lateral interaction regime, depending on the nature of the stimulus and on the cognitive task at hand, and that the transition from one regime to the other is governed by synaptic inhibition. We will test these hypotheses by recording from individual V1 neurons while monitoring the activity of nearby populations of cortical neurons via multiprobe electrodes. In Aim 1 we will relate the activity of V1 neurons to that of nearby populations. We will use simple measures of correlation and nonlinear models that predict individual spikes to measure how responses depend on a feedforward contribution (the receptive field ) and on a lateral contribution (the connection field ). We will test our first hypothesis, concerning the role of the stimulus in changing this dependence. In Aim 2 we will extend these results to a behaving animal. We will record from V1 of mice performing a 2-alternative forced-choice psychophysical task, and we will test our second hypothesis, concerning the role of the cognitive task in determining the operating regime of the cortex. In Aim 3 we will seek a biophysical interpretation of the functional mechanisms and effective connectivity revealed by the previous Aims. We will test our third hypothesis, concerning the role of synaptic inhibition. The tools involved will include intracellular recordings and optical stimulation in transgenic mice whose cortical neurons are sensitive to light.
Max ERC Funding
2 499 921 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym FRU CIRCUIT
Project Neural basis of Drosophila mating behaviours
Researcher (PI) Barry Dickson
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Summary
How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Max ERC Funding
2 492 164 €
Duration
Start date: 2009-07-01, End date: 2013-09-30
Project acronym IMMUNE/MEMORY AGING
Project Can immune system rejuvenation restore age-related memory loss?
Researcher (PI) Michal Eisenbach-Schwartz
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary With increased life expectancy, there has been a critical growth in the portion of the population that suffers from age-related cognitive decline and dementia. Attempts are therefore being made to find ways to slow brain-aging processes; successful therapies would have a significant impact on the quality of life of individuals, and decrease healthcare expenditures. Aging of the immune system has never been suggested as a factor in memory loss. My group formulated the concept of protective autoimmunity , suggesting a linkage between immunity and self-maintenance in the context of the brain in health and disease. Recently, we showed that T lymphocytes recognizing brain-self antigens have a pivotal role in maintaining hippocampal plasticity, as manifested by reduced neurogenesis and impaired cognitive abilities in T-cell deficient mice. Taken together, our novel observations that T cell immunity contributes to hippocampal plasticity, and the fact that T cell immunity decreases with progressive aging create the basis for the present proposal. We will focus on the following questions: (a) Which aspects of cognition are supported by the immune system- learning, memory or both; (b) whether aging of the immune system is sufficient to induce aging of the brain; (c) whether activation of the immune system is sufficient to reverse age-related cognitive decline; (d) the mechanism underlying the effect of peripheral immunity on brain cognition; and (e) potential therapeutic implications of our findings. Our preliminary results demonstrate that the immune system contributes to spatial memory, and that imposing an immune deficiency is sufficient to cause a reversible memory deficit. These findings give strong reason for optimism that memory loss in the elderly is preventable and perhaps reversible by immune-based therapies; we hope that, in the not too distant future, our studies will enable development of a vaccine to prevent CNS aging and cognitive loss in elderly.
Summary
With increased life expectancy, there has been a critical growth in the portion of the population that suffers from age-related cognitive decline and dementia. Attempts are therefore being made to find ways to slow brain-aging processes; successful therapies would have a significant impact on the quality of life of individuals, and decrease healthcare expenditures. Aging of the immune system has never been suggested as a factor in memory loss. My group formulated the concept of protective autoimmunity , suggesting a linkage between immunity and self-maintenance in the context of the brain in health and disease. Recently, we showed that T lymphocytes recognizing brain-self antigens have a pivotal role in maintaining hippocampal plasticity, as manifested by reduced neurogenesis and impaired cognitive abilities in T-cell deficient mice. Taken together, our novel observations that T cell immunity contributes to hippocampal plasticity, and the fact that T cell immunity decreases with progressive aging create the basis for the present proposal. We will focus on the following questions: (a) Which aspects of cognition are supported by the immune system- learning, memory or both; (b) whether aging of the immune system is sufficient to induce aging of the brain; (c) whether activation of the immune system is sufficient to reverse age-related cognitive decline; (d) the mechanism underlying the effect of peripheral immunity on brain cognition; and (e) potential therapeutic implications of our findings. Our preliminary results demonstrate that the immune system contributes to spatial memory, and that imposing an immune deficiency is sufficient to cause a reversible memory deficit. These findings give strong reason for optimism that memory loss in the elderly is preventable and perhaps reversible by immune-based therapies; we hope that, in the not too distant future, our studies will enable development of a vaccine to prevent CNS aging and cognitive loss in elderly.
Max ERC Funding
1 650 000 €
Duration
Start date: 2009-01-01, End date: 2012-12-31
Project acronym INTERPLASTICITY
Project Long-term synaptic plasticity in interneurons: mechanisms and computational significance
Researcher (PI) Dimitri Michael Kullmann
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Memory encoding occurs by strengthening or weakening of synapses among principal neurons. However, excitatory synapses on some inhibitory neurons in the hippocampus also exhibit use-dependent long-term potentiation and depression (LTP and LTD), with important consequences for network homeostasis and information processing. This proposal addresses the following areas: 1. Although the rules determining which forms of plasticity occur at which synapses are emerging in the hippocampus, relatively little is known in other parts of the brain involved in cognition, movement initiation and emotion. We will use electrophysiology, optical imaging and mouse genetics to map out the expression of activity-dependent plasticity at excitatory synapses on inhibitory neurons in the cortex, striatum and amygdala, and relate these to the biophysical and pharmacological properties of the neurons and synapses involved. 2. Although one form of interneuron LTP resembles plasticity in pyramidal neurons, another form requires Ca2+-permeable AMPA receptors and metabotropic glutamate receptors for its induction, and shows features suggestive of pre-synaptic expression. A similar dichotomy exists in two forms of LTD, which depend on either NMDA or Ca2+-permeable AMPA and metabotropic glutamate receptors. We will test the involvement of candidate intracellular and trans-synaptic signalling cascades to understand the mechanisms triggered by distinct conjunction patterns of pre- and post-synaptic activity. 3. What is the computational significance of LTP and LTD in interneurons? The elemental computational roles of different GABAergic interneurons and their firing patterns during behaviourally relevant brain states are beginning to emerge. How synaptic strengthening and/or weakening interact with these network functions is however poorly understood. We will address this through a combination of hypothesis-driven experiments and numerical simulations.
Summary
Memory encoding occurs by strengthening or weakening of synapses among principal neurons. However, excitatory synapses on some inhibitory neurons in the hippocampus also exhibit use-dependent long-term potentiation and depression (LTP and LTD), with important consequences for network homeostasis and information processing. This proposal addresses the following areas: 1. Although the rules determining which forms of plasticity occur at which synapses are emerging in the hippocampus, relatively little is known in other parts of the brain involved in cognition, movement initiation and emotion. We will use electrophysiology, optical imaging and mouse genetics to map out the expression of activity-dependent plasticity at excitatory synapses on inhibitory neurons in the cortex, striatum and amygdala, and relate these to the biophysical and pharmacological properties of the neurons and synapses involved. 2. Although one form of interneuron LTP resembles plasticity in pyramidal neurons, another form requires Ca2+-permeable AMPA receptors and metabotropic glutamate receptors for its induction, and shows features suggestive of pre-synaptic expression. A similar dichotomy exists in two forms of LTD, which depend on either NMDA or Ca2+-permeable AMPA and metabotropic glutamate receptors. We will test the involvement of candidate intracellular and trans-synaptic signalling cascades to understand the mechanisms triggered by distinct conjunction patterns of pre- and post-synaptic activity. 3. What is the computational significance of LTP and LTD in interneurons? The elemental computational roles of different GABAergic interneurons and their firing patterns during behaviourally relevant brain states are beginning to emerge. How synaptic strengthening and/or weakening interact with these network functions is however poorly understood. We will address this through a combination of hypothesis-driven experiments and numerical simulations.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym NANO-DYN-SYN
Project Nano-Scale Organization Dynamics and Functions of Synapses: from single molecule tracking to the physiopathology of excitatory synaptic transmission
Researcher (PI) Daniel Choquet
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Synapses are arguably the most elaborate signaling machine of cells. This complex intercellular junction is specialized for rapid (millisecond) directional signaling. In addition, synapses change in response to patterns of neural activity and these changes can endure, modifying neuronal circuitry. These competing properties of persistence and plasticity must be encoded by the precise content and arrangement of molecules that comprise the presynaptic and postsynaptic specializations. The objective of this project is to uncover the internal organization and dynamics of the postsynaptic specialization at excitatory glutamatergic synapses of the mammalian brain at an unprecedented nano-scale resolution. For this aim, neurobiologists, physicists and chemists join forces in a team with proven track record of collaboration. We will combine cellular and molecular neurobiology approaches with development of novel optical technologies, biosensors and combined quantitative light and electron microscopic imaging techniques. This will provide a new level of analysis to the fundamental problem of molecular information storage. Photothermal imaging of nano-gold particles will allow unprecedented quantitative histochemistry and tracking of protein trafficking up to the level of intact tissue. Development of Cryo-Photoactivated Light Microscopy will allow the correlative localization of synaptic elements at the light and electron-microscopic level. Novel biosensors and chemical tools will be developed for the investigation of the dynamic macromolecular events underlying synaptic plasticity. We will identify new mechanisms that control fast synaptic transmission and its long term activity dependent modification. We will unravel how fast receptor diffusion controls frequency dependent synaptic transmission and how regulation of receptor trafficking participates in synaptic plasticity.
Summary
Synapses are arguably the most elaborate signaling machine of cells. This complex intercellular junction is specialized for rapid (millisecond) directional signaling. In addition, synapses change in response to patterns of neural activity and these changes can endure, modifying neuronal circuitry. These competing properties of persistence and plasticity must be encoded by the precise content and arrangement of molecules that comprise the presynaptic and postsynaptic specializations. The objective of this project is to uncover the internal organization and dynamics of the postsynaptic specialization at excitatory glutamatergic synapses of the mammalian brain at an unprecedented nano-scale resolution. For this aim, neurobiologists, physicists and chemists join forces in a team with proven track record of collaboration. We will combine cellular and molecular neurobiology approaches with development of novel optical technologies, biosensors and combined quantitative light and electron microscopic imaging techniques. This will provide a new level of analysis to the fundamental problem of molecular information storage. Photothermal imaging of nano-gold particles will allow unprecedented quantitative histochemistry and tracking of protein trafficking up to the level of intact tissue. Development of Cryo-Photoactivated Light Microscopy will allow the correlative localization of synaptic elements at the light and electron-microscopic level. Novel biosensors and chemical tools will be developed for the investigation of the dynamic macromolecular events underlying synaptic plasticity. We will identify new mechanisms that control fast synaptic transmission and its long term activity dependent modification. We will unravel how fast receptor diffusion controls frequency dependent synaptic transmission and how regulation of receptor trafficking participates in synaptic plasticity.
Max ERC Funding
3 100 000 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
Project acronym NEURO-BEHAVIOR
Project From Neuron to Behavior
Researcher (PI) Michael Brecht
Host Institution (HI) HUMBOLDT-UNIVERSITAET ZU BERLIN
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary In the present proposal I will describe a novel research agenda for understanding the neural basis of mammalian behavior. Three central problems prevent current research from explaining mammalian behavior in terms of neural mechanisms. First, there is a preponderance of correlative evidence in systems neuroscience. Second there is generally insufficient information about the individual neuron(s) under study. Third, there is a lack of integration of information. Current neuroscience is characterized by strongly diverging research interests and this highly divergent and specialized research program cannot lead to systemic understanding of brain function. We will confront these problems by three novel research approaches: (1) We will establish a causal link between cellular activity and behavior by a single-cell-stimulation / reverse physiology approach. (2) We will obtain rich information about single neurons by whole-cell recordings in awake behaving animals. (3) We will perform a whole-brain-analysis of a novel model organism, the Etruscan shrew, in which we will record the activity of all neurons in the shrew s brain. The research proposed here is unique, because as no other research group investigates brain function by a single-cell-stimulation, by intracellular recordings in freely moving animals, or by whole-brain analysis. The research outlined here will probe the relationship of neural activity and behavior in an entirely unprecedented fashion.
Summary
In the present proposal I will describe a novel research agenda for understanding the neural basis of mammalian behavior. Three central problems prevent current research from explaining mammalian behavior in terms of neural mechanisms. First, there is a preponderance of correlative evidence in systems neuroscience. Second there is generally insufficient information about the individual neuron(s) under study. Third, there is a lack of integration of information. Current neuroscience is characterized by strongly diverging research interests and this highly divergent and specialized research program cannot lead to systemic understanding of brain function. We will confront these problems by three novel research approaches: (1) We will establish a causal link between cellular activity and behavior by a single-cell-stimulation / reverse physiology approach. (2) We will obtain rich information about single neurons by whole-cell recordings in awake behaving animals. (3) We will perform a whole-brain-analysis of a novel model organism, the Etruscan shrew, in which we will record the activity of all neurons in the shrew s brain. The research proposed here is unique, because as no other research group investigates brain function by a single-cell-stimulation, by intracellular recordings in freely moving animals, or by whole-brain analysis. The research outlined here will probe the relationship of neural activity and behavior in an entirely unprecedented fashion.
Max ERC Funding
2 499 600 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
Project acronym NUCLEAR CALCIUM
Project The biology of nuclear calcium: general principles of adaptations and strategies to develop a light-induced signaling enhancer
Researcher (PI) Hilmar Bading
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Adaptation is a characteristic of life. Changes in gene expression allow cells and organisms to transform signals from the environment into long-lasting adaptive responses that range from learning and memory, addiction and chronic pain, to immunity and plant-microbe symbiosis. The project is based on the idea that the rules and signals governing the rich repertoire of adaptations are simple and used nearly universally. The research program consequently follows the concept that persistent adaptations take place when calcium a widely used modulator of cell functions enters the cell nucleus to activate transcription. In the nervous system, nuclear calcium controls CREB-mediated transcription following synaptic activity and is required for memory and activity-dependent survival. Dysfunction of nuclear calcium signaling may lead to cognitive decline and neurodegeneration. We propose to develop methods for in vivo visualization of nuclear calcium signals in awake animals performing learning tasks and to establish, using key examples of adaptive responses, nuclear calcium a an evolutionary conserved regulator of adaptations. On the basis of common principles governing adaptive responses it becomes possible to develop general strategies to modulate adaptations irrespective of cell type or phylogenetic borders. At the heart of the proposal is the development of the proto-type of a nuclear calcium signaling enhancer. We exploit the optical properties of channelrhodopsin and aequorin to construct a light-induced signaling enhancer to boost physiological nuclear calcium responses and to restore them in disease or aging. The proposal has a focus on neuroscience and aims to provide proof-of-principle for unconventional treatments of neurodegenerations and age-related cognitive decline. In addition, the nuclear calcium concept is applied to immunology and plant biology to devise means of modulating immune responses and increasing plant growth by boosting symbiosis signaling.
Summary
Adaptation is a characteristic of life. Changes in gene expression allow cells and organisms to transform signals from the environment into long-lasting adaptive responses that range from learning and memory, addiction and chronic pain, to immunity and plant-microbe symbiosis. The project is based on the idea that the rules and signals governing the rich repertoire of adaptations are simple and used nearly universally. The research program consequently follows the concept that persistent adaptations take place when calcium a widely used modulator of cell functions enters the cell nucleus to activate transcription. In the nervous system, nuclear calcium controls CREB-mediated transcription following synaptic activity and is required for memory and activity-dependent survival. Dysfunction of nuclear calcium signaling may lead to cognitive decline and neurodegeneration. We propose to develop methods for in vivo visualization of nuclear calcium signals in awake animals performing learning tasks and to establish, using key examples of adaptive responses, nuclear calcium a an evolutionary conserved regulator of adaptations. On the basis of common principles governing adaptive responses it becomes possible to develop general strategies to modulate adaptations irrespective of cell type or phylogenetic borders. At the heart of the proposal is the development of the proto-type of a nuclear calcium signaling enhancer. We exploit the optical properties of channelrhodopsin and aequorin to construct a light-induced signaling enhancer to boost physiological nuclear calcium responses and to restore them in disease or aging. The proposal has a focus on neuroscience and aims to provide proof-of-principle for unconventional treatments of neurodegenerations and age-related cognitive decline. In addition, the nuclear calcium concept is applied to immunology and plant biology to devise means of modulating immune responses and increasing plant growth by boosting symbiosis signaling.
Max ERC Funding
2 400 000 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym STEMRENEWAL
Project Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain
Researcher (PI) Patrik Ernfors
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Summary
The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Max ERC Funding
2 492 593 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
