Project acronym CELLTYPESANDCIRCUITS
Project Neural circuit function in the retina of mice and humans
Researcher (PI) Botond Roska
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (multitasking cell types), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform a single computation or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.
Summary
The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (multitasking cell types), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform a single computation or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.
Max ERC Funding
1 499 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym CELPRED
Project Circuit elements of the cortical circuit for predictive processing
Researcher (PI) Georg KELLER
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Summary
One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Max ERC Funding
2 000 000 €
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 CERDEV
Project Transcriptional controls over cerebellar neuron differentiation and circuit assembly
Researcher (PI) Ludovic TELLEY
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Summary
The cerebellum is a critical regulator of motor function, which acts to integrate ongoing body states, sensory inputs and desired outcomes to adjust motor output. This motor control is achieved by a relatively small number of neuron types receiving two main sources of inputs and forming a single output pathway, the axons of Purkinje cells. Although the cerebellum is one of the first structures of the brain to differentiate, it undergoes a prolonged differentiation period such that mature cellular and circuit configuration is achieved only late after birth. Despite the functional importance of this structure, the molecular mechanisms that control type-specific cerebellar neurons generation, differentiation, and circuit assembly are poorly understood and are the topic of the present study.
In my research program, I propose to investigate the transcriptional programs that control the generation of distinct subtypes of cerebellar neurons from progenitors, including Purkinje cells, granule cells and molecular layer interneurons (Work Package 1); the diversity of Purkinje cells across cerebellar regions (Work Package 2) and the postnatal differentiation and circuit integration of granule cells and molecular layer interneurons (Work Package 3). The general bases of the approach I propose consist in: i) specifically label cerebellar neuron progenitors and their progeny at sequential developmental time points pre- and post-natally using birthdate-based tagging, ii) FAC-sort these distinct cell types, iii) isolate these cells and identify their transcriptional signatures with single-cell resolution, iv) functionally interrogate top candidate genes and associated transcriptional programs using in vivo gain- and loss-of-function approaches. Together, these experiments aim at deciphering the cell-intrinsic processes controlling cerebellar circuit formation, towards a better understanding of the molecular mechanisms underlying cerebellar function and dysfunction.
Max ERC Funding
1 499 885 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym CerebralHominoids
Project Evolutionary biology of human and great ape brain development in cerebral organoids
Researcher (PI) Madeline LANCASTER
Host Institution (HI) UNITED KINGDOM RESEARCH AND INNOVATION
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary Humans are endowed with a number of advanced cognitive abilities not seen in other species. So what allows the human brain to stand out from the rest in these capabilities? In general, the brains of primates, including humans, have more neurons per unit volume than other mammals. But humans are also in the fortunate position of having the largest of the primate brains, making the number of neurons in the human cerebral cortex greatly expanded. Thus, the difference seems to be a matter of quantity, not quality. My laboratory is interested in understanding how neuron number, and thus brain size, is determined in human brain development.
The research proposed here is aimed at taking an evolutionary approach to this question and comparing brain development in an in vitro 3D model system, cerebral organoids. This method, which relies on self-organization from differentiating pluripotent stem cells, recapitulates remarkably well the endogenous developmental program of the human brain. Having previously established the brain organoid approach, and more recently improved upon it with the application of bioengineering, my laboratory is in a unique position to carry out functional studies of human brain development. I propose to use this approach to compare developing human brain tissue to that of other hominid species and tease apart unique features of human neural stem cells and progenitors that allow them to generate more neurons and therefore a greater cerebral cortical size. Furthermore, we will perform transcriptomic and functional screening to identify factors underlying this expansion, followed by careful genetic substitution to test the contributions of putative evolutionary changes. In this way, we will functionally test putative human evolutionary changes in a manner not previously possible.
Summary
Humans are endowed with a number of advanced cognitive abilities not seen in other species. So what allows the human brain to stand out from the rest in these capabilities? In general, the brains of primates, including humans, have more neurons per unit volume than other mammals. But humans are also in the fortunate position of having the largest of the primate brains, making the number of neurons in the human cerebral cortex greatly expanded. Thus, the difference seems to be a matter of quantity, not quality. My laboratory is interested in understanding how neuron number, and thus brain size, is determined in human brain development.
The research proposed here is aimed at taking an evolutionary approach to this question and comparing brain development in an in vitro 3D model system, cerebral organoids. This method, which relies on self-organization from differentiating pluripotent stem cells, recapitulates remarkably well the endogenous developmental program of the human brain. Having previously established the brain organoid approach, and more recently improved upon it with the application of bioengineering, my laboratory is in a unique position to carry out functional studies of human brain development. I propose to use this approach to compare developing human brain tissue to that of other hominid species and tease apart unique features of human neural stem cells and progenitors that allow them to generate more neurons and therefore a greater cerebral cortical size. Furthermore, we will perform transcriptomic and functional screening to identify factors underlying this expansion, followed by careful genetic substitution to test the contributions of putative evolutionary changes. In this way, we will functionally test putative human evolutionary changes in a manner not previously possible.
Max ERC Funding
1 444 911 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CHEMOSENSORYCIRCUITS
Project Function of Chemosensory Circuits
Researcher (PI) Emre Yaksi
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary Smell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas.
To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.
Summary
Smell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas.
To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.
Max ERC Funding
1 499 471 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym CHIME
Project The Role of Cortico-Hippocampal Interactions during Memory Encoding
Researcher (PI) Daniel (Ari) Bendor
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary This research proposal’s goal is to investigate the role of cortico-hippocampal interactions during the encoding and consolidation of a memory. Current memory consolidation models postulate that memory storage in our brains occurs by a dynamic process- a recent episodic experience is initially encoded in the hippocampus, and during off-line states such as sleep, the encoded memory is gradually transferred to neocortex for long-term storage. One potential neural mechanism by which this could occur is replay, a phenomenon where neural activity patterns in the hippocampus evoked by a previous experience reactivate spontaneously during non-REM sleep, leading to coordinated cortical reactivation. While previous work suggests that hippocampal replay is important for encoding new memories, how memory consolidation is accomplished through cortico-hippocampal interactions is not well understood.
This research project has three major aims- 1) examine how cortical feedback influences which spatial trajectory is replayed by the hippocampus, 2) investigate how the hippocampal replay of a behavioural episode modifies cortical circuits, 3) measure the causal role of cortico-hippocampal interactions in consolidating memories. We will record ensemble activity from freely moving rats during an auditory-spatial association task and during post-behavioural sleep sessions. We will focus our ensemble recordings on two brain regions: 1) the dorsal CA1 region of the hippocampus, where the phenomenon of sleep replay has been most extensively examined, and 2) auditory cortex, a region of the brain critical for both auditory perception and long-term memory storage. This work will use behavioral and molecular-genetic techniques in combination with large-scale electrophysiological recordings, to help elucidate the role of cortico-hippocampal interactions in memory encoding and consolidation.
Summary
This research proposal’s goal is to investigate the role of cortico-hippocampal interactions during the encoding and consolidation of a memory. Current memory consolidation models postulate that memory storage in our brains occurs by a dynamic process- a recent episodic experience is initially encoded in the hippocampus, and during off-line states such as sleep, the encoded memory is gradually transferred to neocortex for long-term storage. One potential neural mechanism by which this could occur is replay, a phenomenon where neural activity patterns in the hippocampus evoked by a previous experience reactivate spontaneously during non-REM sleep, leading to coordinated cortical reactivation. While previous work suggests that hippocampal replay is important for encoding new memories, how memory consolidation is accomplished through cortico-hippocampal interactions is not well understood.
This research project has three major aims- 1) examine how cortical feedback influences which spatial trajectory is replayed by the hippocampus, 2) investigate how the hippocampal replay of a behavioural episode modifies cortical circuits, 3) measure the causal role of cortico-hippocampal interactions in consolidating memories. We will record ensemble activity from freely moving rats during an auditory-spatial association task and during post-behavioural sleep sessions. We will focus our ensemble recordings on two brain regions: 1) the dorsal CA1 region of the hippocampus, where the phenomenon of sleep replay has been most extensively examined, and 2) auditory cortex, a region of the brain critical for both auditory perception and long-term memory storage. This work will use behavioral and molecular-genetic techniques in combination with large-scale electrophysiological recordings, to help elucidate the role of cortico-hippocampal interactions in memory encoding and consolidation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2021-03-31
Project acronym CholAminCo
Project Synergy and antagonism of cholinergic and dopaminergic systems in associative learning
Researcher (PI) Balazs Gyoergy HANGYA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Summary
Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Max ERC Funding
1 499 463 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym CHOLINOMIRS
Project CholinomiRs: MicroRNA Regulators of Cholinergic Signalling in the Neuro-Immune Interface
Researcher (PI) Hermona Soreq
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Summary
"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Max ERC Funding
2 375 600 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
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
