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 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 ENSEMBLE
Project Neural mechanisms for memory retrieval
Researcher (PI) May-Britt Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Summary
Memory is one of the most extraordinary phenomena in biology. The mammalian brain stores billions of bits of information but the most remarkable property of memory is perhaps not its capacity but the speed at which the correct information can be retrieved from a pool of thousands or millions of competing alternatives. Despite more than hundred years of systematic study of the phenomenon, scientists are still largely ignorant about the mechanisms that enable mammalian brains to outperform even the best search engines. One of the greatest challenges has been the dynamic nature of memory. Whereas memories can be retrieved over time periods as short as milliseconds, underlying coding principles are normally inferred from activity time-averaged across many minutes. In the present proposal, I shall introduce a new ¿teleportation procedure¿ developed in my lab to monitor the representation of past and present environments in large ensembles of rat hippocampal neurons at ethologically valid time scales. By monitoring the evolution of hippocampal ensemble representations at millisecond resolution during retrieval of a non-local experience, I shall ask
(i) what is the minimum temporal unit of a hippocampal representation,
(ii) how is one representational unit replaced by the next in a sequence,
(iii) what external signals control switches between alternative representations,
(iv) how are representations synchronized across anatomical space, and
(v) when do adult-like retrieval mechanisms appear during ontogenesis of the nervous system and to what extent can their early absence be linked to infantile amnesia.
The proposed research programme is expected to identify some of the key principles for dynamic representation and retrieval of episodic memory in the mammalian hippocampus.
Max ERC Funding
2 499 074 €
Duration
Start date: 2011-11-01, End date: 2017-10-31
Project acronym GRIDCODE
Project Cortical maps for space
Researcher (PI) Edvard Ingjald Moser
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary The ultimate goal of neuroscience is to understand the neural basis of subjective experience and behaviour. With our discovery of grid cells as the brain´s metric for space in 2005, spatial navigation became one of the first non-sensory ‘cognitive’ functions of the brain to be accessible for mechanistic analysis. Grid cells are cells with spatially localized firing fields that tile environments with a periodic hexagonal firing pattern in a manner that enables accurate self-localization. Because this activity matrix is generated in the brain, in elaborate neural circuits far away from specific sensory inputs, grid cells provide us with unprecedented access to algorithms of neural coding in the higher cortices. The present proposal will take advantage of this emerging opportunity. The overall objective is to decipher how function is coded, divided and integrated among components of the grid-cell circuit of the medial entorhinal cortex and associated regions. Using a combination of transgenic interventions, intracellular recording and multisite multichannel tetrode recording, we shall establish the mechanisms by which grid cells organize into functionally independent modules, as well as the factors specifying quantitative relationships between grid modules. We shall determine how grid modules are formed during development, test the hypothesis that grid patterns are derived from the local recurrent inhibitory network in layer II, and establish how spatial signals in the entorhinal cortex are transformed to place-cell signals in the hippocampus. Collectively, these studies will pioneer the understanding of functional organization and neural-circuit coding in a non-sensory non-motor mammalian cortex.
Summary
The ultimate goal of neuroscience is to understand the neural basis of subjective experience and behaviour. With our discovery of grid cells as the brain´s metric for space in 2005, spatial navigation became one of the first non-sensory ‘cognitive’ functions of the brain to be accessible for mechanistic analysis. Grid cells are cells with spatially localized firing fields that tile environments with a periodic hexagonal firing pattern in a manner that enables accurate self-localization. Because this activity matrix is generated in the brain, in elaborate neural circuits far away from specific sensory inputs, grid cells provide us with unprecedented access to algorithms of neural coding in the higher cortices. The present proposal will take advantage of this emerging opportunity. The overall objective is to decipher how function is coded, divided and integrated among components of the grid-cell circuit of the medial entorhinal cortex and associated regions. Using a combination of transgenic interventions, intracellular recording and multisite multichannel tetrode recording, we shall establish the mechanisms by which grid cells organize into functionally independent modules, as well as the factors specifying quantitative relationships between grid modules. We shall determine how grid modules are formed during development, test the hypothesis that grid patterns are derived from the local recurrent inhibitory network in layer II, and establish how spatial signals in the entorhinal cortex are transformed to place-cell signals in the hippocampus. Collectively, these studies will pioneer the understanding of functional organization and neural-circuit coding in a non-sensory non-motor mammalian cortex.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym iGLURs - A NEW VIEW
Project Exposing nature’s view of ligand recognition in ionotropic glutamate receptors
Researcher (PI) Timothy Peter Lynagh
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Molecular biology strives for the prediction of function, based on the genetic code. Within neuroscience, this is reflected in the intense study of the molecular basis for ligand recognition by neurotransmitter receptors. Consequently, structural and functional studies have rendered a profoundly high-resolution view of ionotropic glutamate receptors (iGluRs), the archetypal excitatory receptor in the brain. But even this view is obsolete: we don’t know why some receptors recognize glutamate yet others recognize other ligands; and we have been unable to functionally test the underlying chemical interactions. In other words, our view differs substantially from nature’s own view of ligand recognition. I plan to lead a workgroup attacking this problem on three fronts. First, bioinformatic identification and electrophysiological characterization of a broad and representative sample of iGluRs from across the spectrum of life will unveil the diversity of ligand recognition in iGluRs. Second, phylogenetic analyses combined with functional experiments will reveal the molecular changes that nature employed in arriving at existing means of ligand recognition in iGluRs. Finally, chemical-scale mutagenesis will be employed to overcome previous technical limitations and dissect the precise chemical interactions that determine the specific recognition of certain ligands. With my experience in combining phylogenetics and functional experiments and in the use of chemical-scale mutagenesis, the objectives are within reach. Together, they form a unique approach that will expose nature’s own view of ligand recognition in iGluRs, revealing the molecular blueprint for protein function in the nervous system.
Summary
Molecular biology strives for the prediction of function, based on the genetic code. Within neuroscience, this is reflected in the intense study of the molecular basis for ligand recognition by neurotransmitter receptors. Consequently, structural and functional studies have rendered a profoundly high-resolution view of ionotropic glutamate receptors (iGluRs), the archetypal excitatory receptor in the brain. But even this view is obsolete: we don’t know why some receptors recognize glutamate yet others recognize other ligands; and we have been unable to functionally test the underlying chemical interactions. In other words, our view differs substantially from nature’s own view of ligand recognition. I plan to lead a workgroup attacking this problem on three fronts. First, bioinformatic identification and electrophysiological characterization of a broad and representative sample of iGluRs from across the spectrum of life will unveil the diversity of ligand recognition in iGluRs. Second, phylogenetic analyses combined with functional experiments will reveal the molecular changes that nature employed in arriving at existing means of ligand recognition in iGluRs. Finally, chemical-scale mutagenesis will be employed to overcome previous technical limitations and dissect the precise chemical interactions that determine the specific recognition of certain ligands. With my experience in combining phylogenetics and functional experiments and in the use of chemical-scale mutagenesis, the objectives are within reach. Together, they form a unique approach that will expose nature’s own view of ligand recognition in iGluRs, revealing the molecular blueprint for protein function in the nervous system.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym RAT MIRROR CELL
Project Deconstructing action planning and action observation in parietal circuits in rats
Researcher (PI) Jonathan Whitlock
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary The posterior parietal cortex (PPC) mediates cognitive motor functions including motor planning and action understanding. The latter process is thought to occur via ‘mirror’ neurons, which fire both when an animal performs an action and when it observes a cohort performing the same action. The extraordinary tuning properties of PPC cells require the convergence of sensory and motor inputs from several areas, but the function of these inputs is ill-defined since it is not yet feasible in humans or primates to reversibly inhibit targeted anatomical projections. I propose to overcome this by studying PPC in rodents, and will apply optogenetic tools and multi-tetrode recordings to characterize the function of selected cortical inputs to PPC. Similar to motor planning functions for hand or eye movements in primates, the rodent PPC encodes upcoming locomotor movements, and a growing literature suggests that rodents have a mirror system. I thus propose two related research programmes focusing on action planning and the mirror mechanism. The first project will determine if behavioral coding in PPC changes between a foraging task, in which behavior is spontaneous, and during navigational planning in a working memory-based T-maze. I will then determine if silencing fronto-parietal anatomical connections at different phases of the T-maze tasks disrupts motor planning and decision making functions in PPC. Next, I will record from PPC while rats observe cohorts performing the T-maze task to determine if the rat PPC contains mirror neurons. If I find mirror cells in rats, I will optically silence visual and frontal inputs to PPC to determine if they confer mirror selectivity to PPC. These experiments will reveal the anatomical circuitry underlying action planning and the mirror system in a way which cannot be achieved in primate models, and will open the door for studying mirror cells in rodent models of human mental disorders, including autism and Fragile-X syndrome.
Summary
The posterior parietal cortex (PPC) mediates cognitive motor functions including motor planning and action understanding. The latter process is thought to occur via ‘mirror’ neurons, which fire both when an animal performs an action and when it observes a cohort performing the same action. The extraordinary tuning properties of PPC cells require the convergence of sensory and motor inputs from several areas, but the function of these inputs is ill-defined since it is not yet feasible in humans or primates to reversibly inhibit targeted anatomical projections. I propose to overcome this by studying PPC in rodents, and will apply optogenetic tools and multi-tetrode recordings to characterize the function of selected cortical inputs to PPC. Similar to motor planning functions for hand or eye movements in primates, the rodent PPC encodes upcoming locomotor movements, and a growing literature suggests that rodents have a mirror system. I thus propose two related research programmes focusing on action planning and the mirror mechanism. The first project will determine if behavioral coding in PPC changes between a foraging task, in which behavior is spontaneous, and during navigational planning in a working memory-based T-maze. I will then determine if silencing fronto-parietal anatomical connections at different phases of the T-maze tasks disrupts motor planning and decision making functions in PPC. Next, I will record from PPC while rats observe cohorts performing the T-maze task to determine if the rat PPC contains mirror neurons. If I find mirror cells in rats, I will optically silence visual and frontal inputs to PPC to determine if they confer mirror selectivity to PPC. These experiments will reveal the anatomical circuitry underlying action planning and the mirror system in a way which cannot be achieved in primate models, and will open the door for studying mirror cells in rodent models of human mental disorders, including autism and Fragile-X syndrome.
Max ERC Funding
1 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym SurfaceInhibition
Project The role of 5HT3a inhibitory interneurons in sensory processing
Researcher (PI) Koen Gerard Aloïs Vervaeke
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary How do cortical circuits process sensory stimuli that leads to perception? Sensory input is encoded by complex interactions between principal excitatory neurons and a diverse population of inhibitory cells. Distinct inhibitory neurons control different subcellular domains of target principal neurons, suggesting specific roles of different cells during sensory processing. However, the individual contribution of these inhibitory subtypes to sensory processing remains poorly understood. This is mainly due to the technical challenges of recording the activity of identified cell types in-vivo, in response to quantified sensory stimuli. Therefore, I propose a novel approach based on four pillars: 1) An optically accessible circuit in the superficial layers of the cortex, comprised of inhibitory cells expressing the serotonin receptor 5HT3a, and the distal dendrites of pyramidal neurons. 2) A novel combination of electrophysiology and 3D two-photon imaging to simultaneously record the activity of morphologically identified 5HT3a cells and their dendritic targets. 3) A head-fixed perceptual decision task, whereby mice use their whiskers to determine the location of an object, allowing an accurate description of the sensory stimulus. 4) The integration of experimental data and computer models to gain mechanistic insights into circuit functions. The 5HT3a cells and the distal dendrites of pyramidal neurons receive ‘top-down’ contextual information from other cortical areas that is essential for constructing meaningful perceptions of sensory stimuli. Thus I hypothesize that 5HT3a cells influence sensory perceptions by controlling the excitability of the pyramidal cell distal dendrites that integrate top-down and sensory input. Thus, I will not only reveal novel functions of inhibitory neurons, I will also shed light on how top-down and sensory input is integrated, and I will provide novel methods to test the functions of other cell types in normal mice and disease models.
Summary
How do cortical circuits process sensory stimuli that leads to perception? Sensory input is encoded by complex interactions between principal excitatory neurons and a diverse population of inhibitory cells. Distinct inhibitory neurons control different subcellular domains of target principal neurons, suggesting specific roles of different cells during sensory processing. However, the individual contribution of these inhibitory subtypes to sensory processing remains poorly understood. This is mainly due to the technical challenges of recording the activity of identified cell types in-vivo, in response to quantified sensory stimuli. Therefore, I propose a novel approach based on four pillars: 1) An optically accessible circuit in the superficial layers of the cortex, comprised of inhibitory cells expressing the serotonin receptor 5HT3a, and the distal dendrites of pyramidal neurons. 2) A novel combination of electrophysiology and 3D two-photon imaging to simultaneously record the activity of morphologically identified 5HT3a cells and their dendritic targets. 3) A head-fixed perceptual decision task, whereby mice use their whiskers to determine the location of an object, allowing an accurate description of the sensory stimulus. 4) The integration of experimental data and computer models to gain mechanistic insights into circuit functions. The 5HT3a cells and the distal dendrites of pyramidal neurons receive ‘top-down’ contextual information from other cortical areas that is essential for constructing meaningful perceptions of sensory stimuli. Thus I hypothesize that 5HT3a cells influence sensory perceptions by controlling the excitability of the pyramidal cell distal dendrites that integrate top-down and sensory input. Thus, I will not only reveal novel functions of inhibitory neurons, I will also shed light on how top-down and sensory input is integrated, and I will provide novel methods to test the functions of other cell types in normal mice and disease models.
Max ERC Funding
1 350 000 €
Duration
Start date: 2015-12-01, End date: 2020-05-31
