Project acronym AGEMEC
Project Age-dependent mechanisms of sporadic Alzheimer’s Disease in patient-derived neurons
Researcher (PI) Jerome Stefan MERTENS
Host Institution (HI) UNIVERSITAET INNSBRUCK
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Sporadic Alzheimer’s Disease (AD) accounts for the overwhelming majority of all AD cases and exclusively affects people at old age. However, mechanistic links between aging and AD pathology remain elusive. We recently discovered that in contrast to iPSC models, direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of aging, and we have started to develop a patient-based iN model system for AD. Our preliminary data suggests that AD iNs show a neuronal but de-differentiated transcriptome signature. In this project, we first combine cellular neuroscience assays and epigenetic landscape profiling to understand how neurons in AD fail to maintain their fully mature differentiated state, which might be key in permitting disease development. Next, using metabolome analysis including mass spec metabolite assessment, we explore a profound metabolic switch in AD iNs that shows surprisingly many aspects of aerobic glycolysis observed also in cancer. While this link might represent an interesting connection between two age-dependent and de-differentiation-associated diseases, it also opens new avenues to harness knowledge from the cancer field to better understand sporadic AD. We further focus on identifying and manipulating key metabolic regulators that appear to malfunction in an age-dependent manner, with the ultimate goal to define potential targets and treatment strategies. Finally, we will focus on early AD mechanisms by extending our model to mild cognitive impairment (MCI) patients. An agnostic transcriptome and epigenetic landscape approach of glutamatergic and serotonergic iNs will help to determine the earliest and probably most treatable disease mechanisms of AD, and to better understand the contribution of neuropsychiatric risk factors. We anticipate that this project will help to illuminate the mechanistic interface of cellular aging and the development of AD, and help to define new strategies for AD.
Summary
Sporadic Alzheimer’s Disease (AD) accounts for the overwhelming majority of all AD cases and exclusively affects people at old age. However, mechanistic links between aging and AD pathology remain elusive. We recently discovered that in contrast to iPSC models, direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of aging, and we have started to develop a patient-based iN model system for AD. Our preliminary data suggests that AD iNs show a neuronal but de-differentiated transcriptome signature. In this project, we first combine cellular neuroscience assays and epigenetic landscape profiling to understand how neurons in AD fail to maintain their fully mature differentiated state, which might be key in permitting disease development. Next, using metabolome analysis including mass spec metabolite assessment, we explore a profound metabolic switch in AD iNs that shows surprisingly many aspects of aerobic glycolysis observed also in cancer. While this link might represent an interesting connection between two age-dependent and de-differentiation-associated diseases, it also opens new avenues to harness knowledge from the cancer field to better understand sporadic AD. We further focus on identifying and manipulating key metabolic regulators that appear to malfunction in an age-dependent manner, with the ultimate goal to define potential targets and treatment strategies. Finally, we will focus on early AD mechanisms by extending our model to mild cognitive impairment (MCI) patients. An agnostic transcriptome and epigenetic landscape approach of glutamatergic and serotonergic iNs will help to determine the earliest and probably most treatable disease mechanisms of AD, and to better understand the contribution of neuropsychiatric risk factors. We anticipate that this project will help to illuminate the mechanistic interface of cellular aging and the development of AD, and help to define new strategies for AD.
Max ERC Funding
1 499 565 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym CeMoMagneto
Project The Cellular and Molecular Basis of Magnetoreception
Researcher (PI) David Anthony Keays
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Summary
Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.
Max ERC Funding
1 499 752 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym Daphne
Project Circuits of Visual Attention
Researcher (PI) Maximilian Jösch
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The evolutionary arms race has optimized and shaped the way animals attend to relevant sensory stimuli in an ever-changing environment. This is a complex task, because the vast majority of sensory experiences are not relevant. In humans, attentional disorders are a serious public health concern because of its high prevalence, but its causes are mostly unknown. In this proposal, I will explore the neuronal mechanisms used by the nervous system to attend visual cues to enable appropriate behaviors.
We will combine cutting edge imaging techniques, optogenetic interventions, behavioral read outs and targeted connectomics to study the neuronal transformations of the mouse Superior Colliculus (SC), an evolutionary conserved midbrain area known to process sensorimotor transformations and to be involved in the allocation of attention. First, this work will reveal a detailed description of visual representation in the SC, focusing on understanding how defined retinal information-streams, like motion and color, contribute to these properties. Second, we will characterize sensorimotor transformations instructed by the SC. The combination of the previous two objectives will determine mechanisms of visual saliency and sensory driven attention (“bottom-up” attention). Finally, we will explore the neuronal mechanisms of attention by studying the modulatory effect of higher brain areas (“top-down” attention) on sensory transformation and multisensory integration in the SC.
Taken together, this proposal aims to understand principles underlying sensorimotor transformation and build a framework to study attention in health and disease.
Summary
The evolutionary arms race has optimized and shaped the way animals attend to relevant sensory stimuli in an ever-changing environment. This is a complex task, because the vast majority of sensory experiences are not relevant. In humans, attentional disorders are a serious public health concern because of its high prevalence, but its causes are mostly unknown. In this proposal, I will explore the neuronal mechanisms used by the nervous system to attend visual cues to enable appropriate behaviors.
We will combine cutting edge imaging techniques, optogenetic interventions, behavioral read outs and targeted connectomics to study the neuronal transformations of the mouse Superior Colliculus (SC), an evolutionary conserved midbrain area known to process sensorimotor transformations and to be involved in the allocation of attention. First, this work will reveal a detailed description of visual representation in the SC, focusing on understanding how defined retinal information-streams, like motion and color, contribute to these properties. Second, we will characterize sensorimotor transformations instructed by the SC. The combination of the previous two objectives will determine mechanisms of visual saliency and sensory driven attention (“bottom-up” attention). Finally, we will explore the neuronal mechanisms of attention by studying the modulatory effect of higher brain areas (“top-down” attention) on sensory transformation and multisensory integration in the SC.
Taken together, this proposal aims to understand principles underlying sensorimotor transformation and build a framework to study attention in health and disease.
Max ERC Funding
1 446 542 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym ELEGANSNEUROCIRCUITS
Project Neuromodulation of Oxygen Chemosensory Circuits in Caenorhabditis elegans
Researcher (PI) Manuel Zimmer
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary An animal’s decision on how to respond to the environment is based not only on the sensory information available, but further depends on internal factors such as stress, sleep / wakefulness, hunger / satiety and experience. Neurotransmitters and neuropeptides in the brain modulate neural circuits accordingly so that appropriate behaviors are generated. Aberrant neuromodulation is implicated in diseases such as insomnia, obesity or anorexia. Given the complexity of most neural systems studied, we lack good models of how neuromodulators systemically affect the activities of neural networks.
To overcome this problem, I propose to study neural circuits in the nematode C. elegans, which is a genetically tractable model organism with a simple and anatomically defined nervous system. I will focus on the neural circuits involved in oxygen chemosensory behaviors. Worms can smell oxygen and they use this information to navigate through heterogeneous environments. This enables them to find food and to engage in social interactions. Oxygen chemosensory behaviors are highly modulated by experience and nutritional status, but the underlying mechanisms are not understood.
I established behavioral assays that allow studying the modulation of oxygen behaviors in a rigorously quantifiable manner. I also acquired expertise in micro-fabrication technologies and developed imaging devices to measure the activity of neurons in live animals. The first two aims of this proposal focus on the application of these technologies to study (A) how neuropeptides mediate experience dependent modulation of oxygen chemosensory circuits; and (B) how food availability and nutritional status modulate the same neural circuits. Aim (C) is an innovative engineering approach in which I will develop new microfluidic technologies that allow the simultaneous recording of oxygen evoked behaviors and neural activity. This will be beneficial for aims A and B and will pave way for new future research directions.
Summary
An animal’s decision on how to respond to the environment is based not only on the sensory information available, but further depends on internal factors such as stress, sleep / wakefulness, hunger / satiety and experience. Neurotransmitters and neuropeptides in the brain modulate neural circuits accordingly so that appropriate behaviors are generated. Aberrant neuromodulation is implicated in diseases such as insomnia, obesity or anorexia. Given the complexity of most neural systems studied, we lack good models of how neuromodulators systemically affect the activities of neural networks.
To overcome this problem, I propose to study neural circuits in the nematode C. elegans, which is a genetically tractable model organism with a simple and anatomically defined nervous system. I will focus on the neural circuits involved in oxygen chemosensory behaviors. Worms can smell oxygen and they use this information to navigate through heterogeneous environments. This enables them to find food and to engage in social interactions. Oxygen chemosensory behaviors are highly modulated by experience and nutritional status, but the underlying mechanisms are not understood.
I established behavioral assays that allow studying the modulation of oxygen behaviors in a rigorously quantifiable manner. I also acquired expertise in micro-fabrication technologies and developed imaging devices to measure the activity of neurons in live animals. The first two aims of this proposal focus on the application of these technologies to study (A) how neuropeptides mediate experience dependent modulation of oxygen chemosensory circuits; and (B) how food availability and nutritional status modulate the same neural circuits. Aim (C) is an innovative engineering approach in which I will develop new microfluidic technologies that allow the simultaneous recording of oxygen evoked behaviors and neural activity. This will be beneficial for aims A and B and will pave way for new future research directions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2017-06-30
Project acronym EMOTIONCIRCUITS
Project Circuit mechanics of emotions in the limbic system
Researcher (PI) Wulf Eckhard Haubensak
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary Numerous studies established the role of the limbic system in fear and reward: it integrates sensory information, encodes emotional states and instructs other brain centers to regulate physiology and behavior. The limbic system, however, consists of many distinct and highly interconnected neuronal populations. Resolving how emotions are processed in this network at the level of single neural circuits remains a major challenge.
As entry point into the complexity of emotion circuitry, we propose to study, in exemplary fashion, how fear, as the most basic paradigm for emotions, is processed in key limbic hubs. Genetic manipulation of brain circuitry with electrophysiological methods and Pavlovian conditioning in mice, are powerful tools to explore which and how individual circuits in these hubs control emotional states, and, in turn, how genes and psychoactive drugs modulate circuit activity, emotional states and behavior.
We envision this ERC funded research to uncover general principles of the network organization of both emotions and behaviors. It is our hope that we contribute useful tools and methodological framework for investigating other brain functions in a similar manner.
Summary
Numerous studies established the role of the limbic system in fear and reward: it integrates sensory information, encodes emotional states and instructs other brain centers to regulate physiology and behavior. The limbic system, however, consists of many distinct and highly interconnected neuronal populations. Resolving how emotions are processed in this network at the level of single neural circuits remains a major challenge.
As entry point into the complexity of emotion circuitry, we propose to study, in exemplary fashion, how fear, as the most basic paradigm for emotions, is processed in key limbic hubs. Genetic manipulation of brain circuitry with electrophysiological methods and Pavlovian conditioning in mice, are powerful tools to explore which and how individual circuits in these hubs control emotional states, and, in turn, how genes and psychoactive drugs modulate circuit activity, emotional states and behavior.
We envision this ERC funded research to uncover general principles of the network organization of both emotions and behaviors. It is our hope that we contribute useful tools and methodological framework for investigating other brain functions in a similar manner.
Max ERC Funding
1 499 922 €
Duration
Start date: 2013-01-01, End date: 2018-06-30
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 GIANTSYN
Project Biophysics and circuit function of a giant cortical glutamatergic synapse
Researcher (PI) Peter Jonas
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network
computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells
and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible
to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical
mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory
circuit, and several hypotheses about its network function have been generated. However, even basic properties
of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN,
is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular
level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the
same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the
network level, we want to unravel the connectivity rules and the in vivo network function of this synapse,
particularly its role in learning and memory. To reach these objectives, we will combine functional and
structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand
postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of
connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based
on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse
in the history of neuroscience in which we reach complete insight into both synaptic biophysics and
network function. In the long run, the results may open new perspectives for the diagnosis and treatment of
brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.
Summary
A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network
computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells
and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible
to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical
mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory
circuit, and several hypotheses about its network function have been generated. However, even basic properties
of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN,
is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular
level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the
same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the
network level, we want to unravel the connectivity rules and the in vivo network function of this synapse,
particularly its role in learning and memory. To reach these objectives, we will combine functional and
structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand
postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of
connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based
on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse
in the history of neuroscience in which we reach complete insight into both synaptic biophysics and
network function. In the long run, the results may open new perspectives for the diagnosis and treatment of
brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.
Max ERC Funding
2 677 500 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym HIPECMEM
Project Memory-Related Information Processing in Neuronal Circuits of the Hippocampus and Entorhinal Cortex
Researcher (PI) Jozsef Csicsvari
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary This proposal will elucidate the circuit mechanism that underlies the spatial memory-related information processing in the interconnected brain areas of the hippocampus and entorhinal cortex (EC). Both of these areas are implicated in spatial memory and encode spatial information in neuronal activity patterns. The mechanisms underlying the emergence and coordination of spatial memory-related activity in these regions are needed to understand how these circuits process mnemonic information. Accordingly, here we aim at elucidating the representation of spatial memory by investigating these mechanisms at the circuit and synaptic levels of organisation. The first objective of this proposal is to characterise oscillatory synchronisation in hippocampo-EC circuits at different stages of memory processing. We hypothesise that network oscillations facilitate circuit interactions during memory processing. Therefore, using optogenetic techniques to disrupt oscillations, we aim at identifying critical periods during mnemonic processing when synchronisation is needed. Secondly, we intend to reveal how mnemonic information is encoded and exchanged between different areas of the hippocampo-EC system. We will test whether spatial memory-associated firing of dorsal hippocampal cells could be triggered by EC and/or ventral hippocampal cells that encode similar mnemonic features. In addition, this project will explore the role of temporal coding in the representation and consolidation of spatial memory traces. The third objective will investigate synaptic changes between connected CA3-CA3 and CA3-CA1 cell pairs during spatial learning. We will use cross-correlation analysis and electrical microstimulation to examine the rules that govern changes in synaptic efficacy by observing the probability of spike transmission.
Overall, the proposal provides a comprehensive approach to understanding how hippocampo-EC circuits organise and store information during mnemonic processes.
Summary
This proposal will elucidate the circuit mechanism that underlies the spatial memory-related information processing in the interconnected brain areas of the hippocampus and entorhinal cortex (EC). Both of these areas are implicated in spatial memory and encode spatial information in neuronal activity patterns. The mechanisms underlying the emergence and coordination of spatial memory-related activity in these regions are needed to understand how these circuits process mnemonic information. Accordingly, here we aim at elucidating the representation of spatial memory by investigating these mechanisms at the circuit and synaptic levels of organisation. The first objective of this proposal is to characterise oscillatory synchronisation in hippocampo-EC circuits at different stages of memory processing. We hypothesise that network oscillations facilitate circuit interactions during memory processing. Therefore, using optogenetic techniques to disrupt oscillations, we aim at identifying critical periods during mnemonic processing when synchronisation is needed. Secondly, we intend to reveal how mnemonic information is encoded and exchanged between different areas of the hippocampo-EC system. We will test whether spatial memory-associated firing of dorsal hippocampal cells could be triggered by EC and/or ventral hippocampal cells that encode similar mnemonic features. In addition, this project will explore the role of temporal coding in the representation and consolidation of spatial memory traces. The third objective will investigate synaptic changes between connected CA3-CA3 and CA3-CA1 cell pairs during spatial learning. We will use cross-correlation analysis and electrical microstimulation to examine the rules that govern changes in synaptic efficacy by observing the probability of spike transmission.
Overall, the proposal provides a comprehensive approach to understanding how hippocampo-EC circuits organise and store information during mnemonic processes.
Max ERC Funding
1 441 119 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym HIPPOCHRONOCIRCUITRY
Project The chronocircuitry of the hippocampus during cognitive behaviour
Researcher (PI) Thomas Klausberger
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Neuronal activity of pyramidal cells in the CA1 area of the hippocampus enables spatial navigation, learning and memory and their firing is tightly controlled by GABAergic interneurons. Both, pyramidal cells and interneurons are highly heterogeneous cell types. Different CA1 pyramidal cells project to distinct brain areas including the subiculum, entorhinal, retrosplenial, prefrontal cortex, olfactory bulb, striatum and/or hypothalamus. Distinct classes of interneurons innervate different subcellular domains of pyramidal cells and operate with different molecular machineries. However, how the different types of pyramidal cells and interneurons contribute to cognitive behaviour remains unknown. In the present proposal we will use novel techniques to test the hypothesis that different types of pyramidal cells and interneurons define spatio-temporal circuitries in the hippocampus of freely-moving rodents underlying cognitive processing. We will test if pyramidal cells projecting to different brain areas make different contribution to spatial information coding, prospective coding for future choices and memory consolidation during sleep. Also, we will determine how identified classes of GABAergic interneurons control pyramidal cell activity and network oscillations during cognitive tasks in freely-moving rats. In addition, we will use transgenic mice in order to up- or down-regulate quickly and reversibly the activity of specific classes of neurons and determine their causal contribution to network operations and cognitive behaviour. Our experiments will determine spatio-temporal codes in and beyond the hippocampal circuit by defining simultaneously the neuronal activity and synaptic connectivity of identified neurons during cognitive behaviours, learning and memory.
Summary
Neuronal activity of pyramidal cells in the CA1 area of the hippocampus enables spatial navigation, learning and memory and their firing is tightly controlled by GABAergic interneurons. Both, pyramidal cells and interneurons are highly heterogeneous cell types. Different CA1 pyramidal cells project to distinct brain areas including the subiculum, entorhinal, retrosplenial, prefrontal cortex, olfactory bulb, striatum and/or hypothalamus. Distinct classes of interneurons innervate different subcellular domains of pyramidal cells and operate with different molecular machineries. However, how the different types of pyramidal cells and interneurons contribute to cognitive behaviour remains unknown. In the present proposal we will use novel techniques to test the hypothesis that different types of pyramidal cells and interneurons define spatio-temporal circuitries in the hippocampus of freely-moving rodents underlying cognitive processing. We will test if pyramidal cells projecting to different brain areas make different contribution to spatial information coding, prospective coding for future choices and memory consolidation during sleep. Also, we will determine how identified classes of GABAergic interneurons control pyramidal cell activity and network oscillations during cognitive tasks in freely-moving rats. In addition, we will use transgenic mice in order to up- or down-regulate quickly and reversibly the activity of specific classes of neurons and determine their causal contribution to network operations and cognitive behaviour. Our experiments will determine spatio-temporal codes in and beyond the hippocampal circuit by defining simultaneously the neuronal activity and synaptic connectivity of identified neurons during cognitive behaviours, learning and memory.
Max ERC Funding
1 760 911 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym LinPro
Project Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
Researcher (PI) Simon Hippenmeyer
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary The cerebral cortex consists of an extraordinary number and great diversity of neurons. Yet, how the cortical entity, with all its functional neuronal circuits, arises from the neural stem cells (NSCs) in the developing neuroepithelium is a major unsolved question in Neuroscience. Radial glia progenitors (RGPs) are responsible for producing nearly all neocortical neurons and a certain fraction of cortical glia including astrocytes. Our recent efforts provide evidence for a high degree of non-stochasticity and thus deterministic nature of RGP behavior in the mammalian neocortex. However, the cellular and molecular mechanisms controlling RGP lineage progression through proliferation, neurogenesis and especially gliogenesis are unknown. In a pursuit to obtain definitive insights into these fundamental questions we assess RGP lineage progression at the unprecedented single cell resolution, using the unique genetic MADM (Mosaic Analysis with Double Markers) technology. MADM offers an unparalleled approach to visualize and concomitantly manipulate sparse clones and small subsets of genetically defined neurons. Within the scope of this project we will use multidisciplinary experimental approaches to establish a research program with the following major objectives: We will 1) Functionally dissect the relative contribution of cell-autonomous intrinsic signaling and cell-non-autonomous effects in RGP lineage progression; 2) Define the principles of lineage progression in human RGPs in situ using MADM technology in cerebral organoid system; 3) Decipher the logic of glia lineage progression in the neocortex. The ultimate goal of the proposed research is to establish a definitive quantitative framework and mechanistic model of lineage progression in cortical NSCs. As such, the proposed research shall precipitate into extensive conceptual progress regarding the fundamental cellular and molecular principles of cerebral cortex development.
Summary
The cerebral cortex consists of an extraordinary number and great diversity of neurons. Yet, how the cortical entity, with all its functional neuronal circuits, arises from the neural stem cells (NSCs) in the developing neuroepithelium is a major unsolved question in Neuroscience. Radial glia progenitors (RGPs) are responsible for producing nearly all neocortical neurons and a certain fraction of cortical glia including astrocytes. Our recent efforts provide evidence for a high degree of non-stochasticity and thus deterministic nature of RGP behavior in the mammalian neocortex. However, the cellular and molecular mechanisms controlling RGP lineage progression through proliferation, neurogenesis and especially gliogenesis are unknown. In a pursuit to obtain definitive insights into these fundamental questions we assess RGP lineage progression at the unprecedented single cell resolution, using the unique genetic MADM (Mosaic Analysis with Double Markers) technology. MADM offers an unparalleled approach to visualize and concomitantly manipulate sparse clones and small subsets of genetically defined neurons. Within the scope of this project we will use multidisciplinary experimental approaches to establish a research program with the following major objectives: We will 1) Functionally dissect the relative contribution of cell-autonomous intrinsic signaling and cell-non-autonomous effects in RGP lineage progression; 2) Define the principles of lineage progression in human RGPs in situ using MADM technology in cerebral organoid system; 3) Decipher the logic of glia lineage progression in the neocortex. The ultimate goal of the proposed research is to establish a definitive quantitative framework and mechanistic model of lineage progression in cortical NSCs. As such, the proposed research shall precipitate into extensive conceptual progress regarding the fundamental cellular and molecular principles of cerebral cortex development.
Max ERC Funding
1 996 030 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
