Project acronym BrainDyn
Project Tracking information flow in the brain: A unified and general framework for dynamic communication in brain networks
Researcher (PI) Mathilde BONNEFOND
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The brain is composed of a set of areas specialized in specific computations whose outputs need to be transferred to other specialized areas for cognition to emerge. To account for context-dependent behaviors, the information has to be flexibly routed through the fixed anatomy of the brain. The aim of my proposal is to test a general framework for flexible communication between brain areas based on nested oscillations which I recently developed. The general idea is that internally-driven slow oscillations (<20Hz) either set-up or prevent the communication between brain areas. Stimulus-driven gamma oscillations (>30Hz), nested in the slow oscillations, can then be directed to task-relevant areas of the network. I plan to use a multimodal, multi-scale and transversal (human and monkey) approach in experiments manipulating visual processing, attention and memory to test core predictions of my framework. The theoretical approach and the methodological development used in my project will provide the basis for future fundamental and clinical research.
Summary
The brain is composed of a set of areas specialized in specific computations whose outputs need to be transferred to other specialized areas for cognition to emerge. To account for context-dependent behaviors, the information has to be flexibly routed through the fixed anatomy of the brain. The aim of my proposal is to test a general framework for flexible communication between brain areas based on nested oscillations which I recently developed. The general idea is that internally-driven slow oscillations (<20Hz) either set-up or prevent the communication between brain areas. Stimulus-driven gamma oscillations (>30Hz), nested in the slow oscillations, can then be directed to task-relevant areas of the network. I plan to use a multimodal, multi-scale and transversal (human and monkey) approach in experiments manipulating visual processing, attention and memory to test core predictions of my framework. The theoretical approach and the methodological development used in my project will provide the basis for future fundamental and clinical research.
Max ERC Funding
1 333 718 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym BrainEnergy
Project Control of cerebral blood flow by capillary pericytes in health and disease
Researcher (PI) David ATTWELL
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Summary
Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Max ERC Funding
2 499 954 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BrainInBrain
Project Neural circuits underlying complex brain function across animals - from conserved core concepts to specializations defining a species’ identity
Researcher (PI) Stanley HEINZE
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.
Summary
The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym BrainModes
Project Personalized whole brain simulations: linking connectomics and dynamics in the human brain
Researcher (PI) Petra Ritter
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.
Summary
Background. We have detailed maps of brain structure and function, yet are lacking understanding of how the highly connected units interact and give rise to mental processes. The Virtual Brain (TVB), a whole brain simulation framework, aims to bridge that gap. Yet it is still developing. We are proposing here breakthrough advances that reveal mechanisms of brain function and foster collaboration between research groups. Vision. Clinical applications that simulate individual patient brains and predict trajectories of recovery or decline or test therapies to select the best one for that person. Goal. Using biologically realistic brain models and multimodal functional and structural imaging data to elucidate control mechanisms of the human brain in aging. A database collects key data and allows identifying most generic models and mechanisms below the spatial and temporal resolution of non-invasive imaging techniques taking into account the complex interaction in the brain that without a model would be impossible to keep track of. Objectives. 1) Parameter optimization for large parameter space search and a library of dynamical regimes linking dynamical regimes and underlying mechanisms to biological (cognitive) age. 2) Identifying the role of intrinsic plasticity for network reconfigurations in the resting state and its age dependency. 3) Model based identification of task related plasticity mechanisms and their functional consequences for network reconfigurations in coordination learning in aging. 4) An interactive tool that provides access to the dynamical regimes library and makes pre-computed simulations easily accessible allowing researchers to benefit and learn from existing work. Impact. Understanding development, aging and brain disorders from the perspective of disruption of information processing architectures provides an opportunity for new interventions that re-establish control in brain pathology hence posing a breakthrough in the health and biotech sector.
Max ERC Funding
1 870 588 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym BrainNanoFlow
Project Nanoscale dynamics in the extracellular space of the brain in vivo
Researcher (PI) Juan Alberto VARELA
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Summary
Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Max ERC Funding
1 552 948 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BRAINPOWER
Project Brain energy supply and the consequences of its failure
Researcher (PI) David Ian Attwell
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Summary
Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).
Max ERC Funding
2 499 947 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym BrainReadFBPredCode
Project Brain reading of contextual feedback and predictions
Researcher (PI) Lars Muckli
Host Institution (HI) UNIVERSITY OF GLASGOW
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary We are currently witnessing a paradigm shift in our understanding of human brain function, moving towards a clearer description of cortical processing. Sensory systems are no longer considered as 'passively recording' but rather as dynamically anticipating and adapting to the rapidly changing environment. These new ideas are encompassed in the predictive coding framework, and indeed in a unifying theory of the brain (Friston, 2010). In terms of brain computation, a predictive model is created in higher cortical areas and communicated to lower sensory areas through feedback connections. Based on my pioneering research I propose experiments that are capable of ‘brain-reading’ cortical feedback– which would contribute invaluable data to theoretical frameworks.
The proposed research project will advance our understanding of ongoing brain activity, contextual processing, and cortical feedback - contributing to what is known about general cortical functions. By providing new insights as to the information content of cortical feedback, the proposal will fill one of the most important gaps in today’s knowledge about brain function. Friston’s unifying theory of the brain (Friston, 2010) and contemporary models of the predictive-coding framework (Hawkins and Blakeslee, 2004;Mumford, 1992;Rao and Ballard, 1999) assign feedback processing an essential role in cortical processing. Compared to feedforward information processing, our knowledge about feedback processing is in its infancy. The proposal introduces parametric and explorative brain reading designs to investigate this feedback processing. The chief goal of my proposal will be precision measures of cortical feedback, and a more ambitious objective is to read mental images and inner thoughts.
Summary
We are currently witnessing a paradigm shift in our understanding of human brain function, moving towards a clearer description of cortical processing. Sensory systems are no longer considered as 'passively recording' but rather as dynamically anticipating and adapting to the rapidly changing environment. These new ideas are encompassed in the predictive coding framework, and indeed in a unifying theory of the brain (Friston, 2010). In terms of brain computation, a predictive model is created in higher cortical areas and communicated to lower sensory areas through feedback connections. Based on my pioneering research I propose experiments that are capable of ‘brain-reading’ cortical feedback– which would contribute invaluable data to theoretical frameworks.
The proposed research project will advance our understanding of ongoing brain activity, contextual processing, and cortical feedback - contributing to what is known about general cortical functions. By providing new insights as to the information content of cortical feedback, the proposal will fill one of the most important gaps in today’s knowledge about brain function. Friston’s unifying theory of the brain (Friston, 2010) and contemporary models of the predictive-coding framework (Hawkins and Blakeslee, 2004;Mumford, 1992;Rao and Ballard, 1999) assign feedback processing an essential role in cortical processing. Compared to feedforward information processing, our knowledge about feedback processing is in its infancy. The proposal introduces parametric and explorative brain reading designs to investigate this feedback processing. The chief goal of my proposal will be precision measures of cortical feedback, and a more ambitious objective is to read mental images and inner thoughts.
Max ERC Funding
1 494 714 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
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 BRAINSIGNALS
Project Optical dissection of circuits underlying fast cholinergic signalling during cognitive behaviour
Researcher (PI) Huibert Mansvelder
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour.
In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. Using these techniques, I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function.
Summary
Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour.
In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. Using these techniques, I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function.
Max ERC Funding
1 499 242 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
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
