Project acronym ACMO
Project Systematic dissection of molecular machines and neural circuits coordinating C. elegans aggregation behaviour
Researcher (PI) Mario De Bono
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis.
We propose to:
1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour.
2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid.
This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.
Summary
Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis.
We propose to:
1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour.
2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid.
This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.
Max ERC Funding
2 439 996 €
Duration
Start date: 2011-04-01, End date: 2017-03-31
Project acronym ACTSELECTCONTEXT
Project Action Selection under Contextual Uncertainty: the Role of Learning and Effective Connectivity in the Human Brain
Researcher (PI) Sven Bestmann
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.
Summary
In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.
Max ERC Funding
1 341 805 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym ADDICTIONCIRCUITS
Project Drug addiction: molecular changes in reward and aversion circuits
Researcher (PI) Nils David Engblom
Host Institution (HI) LINKOPINGS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Summary
Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym ANXIETY MECHANISMS
Project Neurocognitive mechanisms of human anxiety: identifying and
targeting disrupted function
Researcher (PI) Sonia Jane Bishop
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment.
One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation.
Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.
Summary
Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment.
One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation.
Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.
Max ERC Funding
1 708 407 €
Duration
Start date: 2011-04-01, End date: 2016-08-31
Project acronym AXOGLIA
Project The role of myelinating glia in preserving axon function
Researcher (PI) Klaus-Armin Nave
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary In the human brain, the 'bottleneck' of neuronal integrity are long axonal projections, which are often the first to degenerate in neuro-psychiatric diseases. We have discovered in mice that oligodendrocytes and Schwann cells are not only essential for the formation of myelin, but also for the functional integrity of axons and their long-term survival. However, the underlying molecular mechanisms have remained obscure. We propose to use experimental mouse genetics to study neuron-glia interactions and to identify axonal signals that control the normal behaviour of myelinating oligodendrocytes. We will then test our hypothesis that axons require oligodendrocytes not only for myelination, but also for the metabolic support of impulse propagation and fast axonal transport. Based on striking pilot observations, we will analyze the mechanisms by which ensheathing glial cells respond to axonal distress and ask in vivo whether they provide glycolysis end products to axonal mitochondria for energy production ('lactate shuttle'). We will also investigate whether myelin lipids are a readily accessible energy store in glia and explore a speculative hypothesis that N-acetyl aspartate is an aspartate-based shuttle of acetyl-CoA residues. If this proposal is successful, we will begin to understand the true function of oligodendrocytes in endogenous neuroprotection and as bystanders of neuronal disease and normal brain aging. This would initiate a paradigm shift for the role of myelinating glial cells, and could open the door for novel therapeutic strategies in a broad range of neurodegenerative diseases, which pose a major burden on the EC health care system.
Summary
In the human brain, the 'bottleneck' of neuronal integrity are long axonal projections, which are often the first to degenerate in neuro-psychiatric diseases. We have discovered in mice that oligodendrocytes and Schwann cells are not only essential for the formation of myelin, but also for the functional integrity of axons and their long-term survival. However, the underlying molecular mechanisms have remained obscure. We propose to use experimental mouse genetics to study neuron-glia interactions and to identify axonal signals that control the normal behaviour of myelinating oligodendrocytes. We will then test our hypothesis that axons require oligodendrocytes not only for myelination, but also for the metabolic support of impulse propagation and fast axonal transport. Based on striking pilot observations, we will analyze the mechanisms by which ensheathing glial cells respond to axonal distress and ask in vivo whether they provide glycolysis end products to axonal mitochondria for energy production ('lactate shuttle'). We will also investigate whether myelin lipids are a readily accessible energy store in glia and explore a speculative hypothesis that N-acetyl aspartate is an aspartate-based shuttle of acetyl-CoA residues. If this proposal is successful, we will begin to understand the true function of oligodendrocytes in endogenous neuroprotection and as bystanders of neuronal disease and normal brain aging. This would initiate a paradigm shift for the role of myelinating glial cells, and could open the door for novel therapeutic strategies in a broad range of neurodegenerative diseases, which pose a major burden on the EC health care system.
Max ERC Funding
2 477 800 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym BIOMOTIV
Project Why do we do what we do? Biological, psychological and computational bases of motivation
Researcher (PI) Mathias Pessiglione
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Summary
We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Max ERC Funding
1 346 000 €
Duration
Start date: 2011-03-01, End date: 2016-08-31
Project acronym BRAINSHAPE
Project Objects in sight: the neural basis of visuomotor transformations for actions towards objects
Researcher (PI) Peter Anna J Janssen
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.
Summary
Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.
Max ERC Funding
1 499 200 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym BRAINSTATES
Project Brain states, synapses and behaviour
Researcher (PI) James Poulet
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Global changes in patterns of neuronal activity or brain state are the first phenomenon recorded in the awake human brain (1). Changes in brain state are present in recordings of neocortical activity from mouse to man. It is now thought that changes in brain state are fundamental to normal brain function and neuronal computation. Despite their importance, we have very little idea about the underlying neuronal mechanisms that generate them or their precise impact on neuronal processing and behaviour. In previous work we have characterised brain state changes in a well characterised model for neuroscience research the mouse whisker system. We have recorded changes in the brain state in mouse cortex during whisker movements (2). In this proposal, we aim to use the mouse whisker system further to investigate the mechanisms and functions of changes in brain state. First we will use state of the art techniques to record and manipulate neuronal activity in the awake, behaving mouse to investigate the network and cellular mechanisms involved in generating brain state. Second we will use 2-photon microscopy to investigate the impact of brain state on excitatory and inhibitory synaptic integration in vivo. Finally we will use behaviourally trained mice to measure the impact of brain state changes on sensory perception and behaviour. This proposal will therefore provide fundamental insights into brain function at every step: mechanisms of changes in brain state, how neurons communicate with eachother and how the brain controls sensory perception and behaviour.
References
1 Berger H (1929) Archiv für Psychiatrie und Nervenkrankheiten 87:527-570.
2 Poulet JFA, Petersen CC (2008) Nature 454:881-885.
Summary
Global changes in patterns of neuronal activity or brain state are the first phenomenon recorded in the awake human brain (1). Changes in brain state are present in recordings of neocortical activity from mouse to man. It is now thought that changes in brain state are fundamental to normal brain function and neuronal computation. Despite their importance, we have very little idea about the underlying neuronal mechanisms that generate them or their precise impact on neuronal processing and behaviour. In previous work we have characterised brain state changes in a well characterised model for neuroscience research the mouse whisker system. We have recorded changes in the brain state in mouse cortex during whisker movements (2). In this proposal, we aim to use the mouse whisker system further to investigate the mechanisms and functions of changes in brain state. First we will use state of the art techniques to record and manipulate neuronal activity in the awake, behaving mouse to investigate the network and cellular mechanisms involved in generating brain state. Second we will use 2-photon microscopy to investigate the impact of brain state on excitatory and inhibitory synaptic integration in vivo. Finally we will use behaviourally trained mice to measure the impact of brain state changes on sensory perception and behaviour. This proposal will therefore provide fundamental insights into brain function at every step: mechanisms of changes in brain state, how neurons communicate with eachother and how the brain controls sensory perception and behaviour.
References
1 Berger H (1929) Archiv für Psychiatrie und Nervenkrankheiten 87:527-570.
2 Poulet JFA, Petersen CC (2008) Nature 454:881-885.
Max ERC Funding
1 463 125 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym CARV
Project Chemical Approaches to Restoring Vision
Researcher (PI) Dirk Trauner
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary Blindness affects millions of people worldwide and has devastating consequences for those affected. It is often caused by a loss of photoreceptors in the retina, whose residual cellular network remains largely unaffected. Various strategies have been chosen to restore vision, such as electrical stimulation with retinal implants. More recently, natural photoreceptor proteins and stem cells have been explored. We propose a radically different ¿photopharmacological¿ approach toward vision restoration that is based on synthetic photoswitches. These are combined in various ways with natural receptor proteins to create hybrid photoreceptors, which can then sensitize neurons toward light. In a way we are ¿teaching old receptors new tricks¿ and let them carry out functions that they have not evolved for in Nature. Our hybrid photoreceptors and photochromic drugs work well in experimental animals and have already been shown to influence their visual behavior. To make these molecules work in humans, we need to improve their photophysical properties and investigate their delivery, stability and pharmacology. This requires an extensive program in synthetic chemistry, which should be accompanied by effective and immediate neurobiological evaluation. Our very general approach to optically controlling neural activity can be applied to other functions and malfunctions of the nervous system, such as pain or epilepsy, but its greatest medical potential currently lies in the restoration of vision.
Summary
Blindness affects millions of people worldwide and has devastating consequences for those affected. It is often caused by a loss of photoreceptors in the retina, whose residual cellular network remains largely unaffected. Various strategies have been chosen to restore vision, such as electrical stimulation with retinal implants. More recently, natural photoreceptor proteins and stem cells have been explored. We propose a radically different ¿photopharmacological¿ approach toward vision restoration that is based on synthetic photoswitches. These are combined in various ways with natural receptor proteins to create hybrid photoreceptors, which can then sensitize neurons toward light. In a way we are ¿teaching old receptors new tricks¿ and let them carry out functions that they have not evolved for in Nature. Our hybrid photoreceptors and photochromic drugs work well in experimental animals and have already been shown to influence their visual behavior. To make these molecules work in humans, we need to improve their photophysical properties and investigate their delivery, stability and pharmacology. This requires an extensive program in synthetic chemistry, which should be accompanied by effective and immediate neurobiological evaluation. Our very general approach to optically controlling neural activity can be applied to other functions and malfunctions of the nervous system, such as pain or epilepsy, but its greatest medical potential currently lies in the restoration of vision.
Max ERC Funding
2 484 613 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
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
