Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragão Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym AXPLAST
Project Deep brain imaging of cellular mechanisms of sensory processing and learning
Researcher (PI) Jan GRUNDEMANN
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Summary
Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics.
Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo.
We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus.
Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.
Max ERC Funding
1 475 475 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
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 CELLPHASE_AD
Project Genetics to understand cellular components of Alzheimer Disease pathogenesis
Researcher (PI) Bart Geert Alfons Paul DE STROOPER
Host Institution (HI) VIB VZW
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process.
Human stem cells (iPS) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field. We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau- pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated. In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 selected AD associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis.
Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.
Summary
Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process.
Human stem cells (iPS) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field. We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau- pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated. In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 selected AD associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis.
Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.
Max ERC Funding
2 374 998 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym COGNIBRAINS
Project Cognition in an Insect Brain
Researcher (PI) Martin GIURFA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Summary
There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Max ERC Funding
2 145 339 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym DEVMEM
Project Learning to remember: the development of the neural mechanisms supporting memory processing.
Researcher (PI) Francesca CACUCCI
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary The ability to form and store memories allows organisms to learn from the past and imagine the future: it is a crucial mechanism underlying flexible and adaptive behaviour. The aim of this proposal is to identify the circuit mechanisms underlying our ability to learn and remember, by tracking the ontogenesis of memory processing. Importantly, we are not born with a fully functioning memory system: generally, adults cannot recollect any events from before their third birthday (‘infantile amnesia’). There are several accounts as to the source of this mnemonic deficit, each placing emphasis on impairments of specific processes (encoding, consolidation, retrieval). However, a general weakness in the study of memory ontogeny is the lack of neural data describing the activity of memory-related circuits during development. To directly address this knowledge gap, we propose to study the ontogeny of brain-wide hippocampus-centred memory networks in the rat. We will study to which extent memory expression relies on spatial signalling, delineate the role of sleep in memory consolidation, determine how hippocampal planning-related neuronal activity influences memory processing, understand whether the rapid forgetting observed in development is due to interference, and explore interactions between the hippocampus, pre-frontal and striatal circuits in orchestrating memory emergence. We are best placed to deliver this ambitious experimental plan due to our extensive experience of in vivo recording in developing rats which we will couple with the application of recently emerged technologies (2-photon imaging, high density electrophysiology, chemogenetic manipulation of neural activity). As our studies of the development of hippocampal spatial representations have delivered powerful insights into their adult function, we expect the work outlined here to critically advance our understanding not only of development, but also of healthy memory processing in adulthood.
Summary
The ability to form and store memories allows organisms to learn from the past and imagine the future: it is a crucial mechanism underlying flexible and adaptive behaviour. The aim of this proposal is to identify the circuit mechanisms underlying our ability to learn and remember, by tracking the ontogenesis of memory processing. Importantly, we are not born with a fully functioning memory system: generally, adults cannot recollect any events from before their third birthday (‘infantile amnesia’). There are several accounts as to the source of this mnemonic deficit, each placing emphasis on impairments of specific processes (encoding, consolidation, retrieval). However, a general weakness in the study of memory ontogeny is the lack of neural data describing the activity of memory-related circuits during development. To directly address this knowledge gap, we propose to study the ontogeny of brain-wide hippocampus-centred memory networks in the rat. We will study to which extent memory expression relies on spatial signalling, delineate the role of sleep in memory consolidation, determine how hippocampal planning-related neuronal activity influences memory processing, understand whether the rapid forgetting observed in development is due to interference, and explore interactions between the hippocampus, pre-frontal and striatal circuits in orchestrating memory emergence. We are best placed to deliver this ambitious experimental plan due to our extensive experience of in vivo recording in developing rats which we will couple with the application of recently emerged technologies (2-photon imaging, high density electrophysiology, chemogenetic manipulation of neural activity). As our studies of the development of hippocampal spatial representations have delivered powerful insights into their adult function, we expect the work outlined here to critically advance our understanding not only of development, but also of healthy memory processing in adulthood.
Max ERC Funding
1 999 520 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym DisConn
Project Neural drivers of functional disconnectivity in brain disorders
Researcher (PI) Alessandro GOZZI
Host Institution (HI) FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Summary
A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Max ERC Funding
1 498 125 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym DiurnalHealth
Project The circadian clock in day-active species: preserving our health in modern society
Researcher (PI) Johanna H. MEIJER
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary Due to a significant increase in the use of artificial light in our 24h economy, the biological clocks of all living organisms, including humans, are severely disrupted. Many severe health disorders are consequences of clock disruption such as diabetes, sleep/mood disorders, cardiovascular disease, and immune dysfunction. The central timekeeper in mammals is the suprachiasmatic nucleus (SCN), and the mechanisms by which light disrupts integrity of the SCN has been well investigated in nocturnal species. In contrast, mechanisms of clock disruption in humans and other diurnal (day-active) species remain poorly defined. I have evidence that the mechanisms that drive SCN function are fundamentally different between nocturnal species and diurnal species. This defines my aim to restore proper clock function in diurnal species, including humans. To test this, in Objective 1 we will identify similarities and differences between nocturnal and diurnal clocks with respect to their i) response to light, ii) neuronal synchronization, iii) output, and iv) response to physical activity. Based on these findings, in Objective 2 we will develop novel strategies to manipulate and restore clock function in diurnal species. These objectives will be achieved using novel, state-of-the-art chronobiology methods including in vivo electrophysiology and Ca2+ and bioluminescence reporters—all in freely behaving day-active animals, as well as in slice preparations containing the SCN. For studies on the human SCN we record with 7-Tesla fMRI. This proposal will help establish a new basis for chronobiology with respect to the most suitable models for studying translational applications. The results will yield immediate benefits in terms of manipulating biological clock function among vulnerable populations in modern society, particularly the elderly, patients in intensive care, and shift workers.
Summary
Due to a significant increase in the use of artificial light in our 24h economy, the biological clocks of all living organisms, including humans, are severely disrupted. Many severe health disorders are consequences of clock disruption such as diabetes, sleep/mood disorders, cardiovascular disease, and immune dysfunction. The central timekeeper in mammals is the suprachiasmatic nucleus (SCN), and the mechanisms by which light disrupts integrity of the SCN has been well investigated in nocturnal species. In contrast, mechanisms of clock disruption in humans and other diurnal (day-active) species remain poorly defined. I have evidence that the mechanisms that drive SCN function are fundamentally different between nocturnal species and diurnal species. This defines my aim to restore proper clock function in diurnal species, including humans. To test this, in Objective 1 we will identify similarities and differences between nocturnal and diurnal clocks with respect to their i) response to light, ii) neuronal synchronization, iii) output, and iv) response to physical activity. Based on these findings, in Objective 2 we will develop novel strategies to manipulate and restore clock function in diurnal species. These objectives will be achieved using novel, state-of-the-art chronobiology methods including in vivo electrophysiology and Ca2+ and bioluminescence reporters—all in freely behaving day-active animals, as well as in slice preparations containing the SCN. For studies on the human SCN we record with 7-Tesla fMRI. This proposal will help establish a new basis for chronobiology with respect to the most suitable models for studying translational applications. The results will yield immediate benefits in terms of manipulating biological clock function among vulnerable populations in modern society, particularly the elderly, patients in intensive care, and shift workers.
Max ERC Funding
2 233 251 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym EAGER
Project Elucidating the effects of ageing on the nucleoporin-directed neural cell type-specific nuclear architecture and gene regulation
Researcher (PI) Tomohisa TODA
Host Institution (HI) DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Ageing is one of the most critical risk factors for neurological and psychiatric diseases. However, the biological links between physiological ageing and pathological development are still largely unknown. A solid understanding of the biology of brain ageing will thus be a key to developing the means to treat these diseases. Since neurons in the brain are mostly generated during development with limited capacity of replacement after birth, they need to maintain their identity and function throughout our lives. This project aims at seeking a link between the fundamental mechanism underlying the long-term maintenance of neural identity and effects of ageing on that.
We recently discovered that a cell type-specific nuclear architecture organized by nucleoporins in cooperation with a key transcription factor (TF), work as a structural gatekeeper for the maintenance of neural progenitor cells (NPs). Strikingly, nucleoporins are the most long-lived proteins in a cell and are known to be damaged during brain ageing. Thus, the proposed experiments will test a specific hypothesis that the nucleoporin-TF directed nuclear architecture is a fundamental principle governing cell type-specific gene regulation, and that pathological ageing impairs that critical relationship.
To test this hypothesis, we will use interdisciplinary approaches. First, the changes of molecular constituents of nucleoporin-TF partnerships from NPs into the post-mitotic neurons are probed. Second, the roles of identified partnerships in the maintenance of neuronal identity and function will be investigated using biochemical, imaging, genome-wide and behavioural approaches. Efforts will be directed toward studying the effects of ageing and Alzheimer’s diseases on the identified mechanisms. The successful completion of this research will uncover a novel aspect of regulation in the maintenance of cellular identity and open up a new field of research in neuroscience.
Summary
Ageing is one of the most critical risk factors for neurological and psychiatric diseases. However, the biological links between physiological ageing and pathological development are still largely unknown. A solid understanding of the biology of brain ageing will thus be a key to developing the means to treat these diseases. Since neurons in the brain are mostly generated during development with limited capacity of replacement after birth, they need to maintain their identity and function throughout our lives. This project aims at seeking a link between the fundamental mechanism underlying the long-term maintenance of neural identity and effects of ageing on that.
We recently discovered that a cell type-specific nuclear architecture organized by nucleoporins in cooperation with a key transcription factor (TF), work as a structural gatekeeper for the maintenance of neural progenitor cells (NPs). Strikingly, nucleoporins are the most long-lived proteins in a cell and are known to be damaged during brain ageing. Thus, the proposed experiments will test a specific hypothesis that the nucleoporin-TF directed nuclear architecture is a fundamental principle governing cell type-specific gene regulation, and that pathological ageing impairs that critical relationship.
To test this hypothesis, we will use interdisciplinary approaches. First, the changes of molecular constituents of nucleoporin-TF partnerships from NPs into the post-mitotic neurons are probed. Second, the roles of identified partnerships in the maintenance of neuronal identity and function will be investigated using biochemical, imaging, genome-wide and behavioural approaches. Efforts will be directed toward studying the effects of ageing and Alzheimer’s diseases on the identified mechanisms. The successful completion of this research will uncover a novel aspect of regulation in the maintenance of cellular identity and open up a new field of research in neuroscience.
Max ERC Funding
1 499 999 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym EngineeringBAP
Project Engineering brain activity patterns for therapeutics of neuropsychiatric and neurological disorders
Researcher (PI) Mehmet Fatih YANIK
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatment
has been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, and
for direct and localized modifications of these circuits. We propose minimally invasive technologies for
measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to
correct the abnormal behavioural phenotypes (in rodents with potential scalability to non-human primates and
humans). First, we present a proof-of-principle study on mutant zebrafish, in which we correct whole-brain
level abnormal activity patterns and behaviours by using large-scale single-neuron resolution measurements,
and by simultaneously modulating multiple sub-networks via neuromodulator cocktails. Next, we present
strong preliminary data in rodents and our plan: (1) For manipulating brain circuits in rodents/primates noninvasively,
we will develop technologies that can deliver receptive-specific neuromodulators to spatially
precise brain targets without opening/damaging the blood brain barrier. These methods will employ engineered
ultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits in
rodents/primates, we will develop flexible low-power neuromorphic μECoG circuits that can detect single
neuron signals from superficial cortical layers of many cortical areas simultaneously. (3) Finally, these novel
technologies will be comprehensively evaluated on a mouse model of obsessive compulsivity and anxiety
using a battery of behavioural tasks to reverse the pathological symptoms (beyond what is achievable by
existing approaches). This project constitutes a major step towards the development and testing of minimallyinvasive
and high-precision technologies for manipulating brain activity patterns, which can impact both our
understanding of the brain and treatment of intractable brain disorders.
Summary
Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatment
has been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, and
for direct and localized modifications of these circuits. We propose minimally invasive technologies for
measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to
correct the abnormal behavioural phenotypes (in rodents with potential scalability to non-human primates and
humans). First, we present a proof-of-principle study on mutant zebrafish, in which we correct whole-brain
level abnormal activity patterns and behaviours by using large-scale single-neuron resolution measurements,
and by simultaneously modulating multiple sub-networks via neuromodulator cocktails. Next, we present
strong preliminary data in rodents and our plan: (1) For manipulating brain circuits in rodents/primates noninvasively,
we will develop technologies that can deliver receptive-specific neuromodulators to spatially
precise brain targets without opening/damaging the blood brain barrier. These methods will employ engineered
ultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits in
rodents/primates, we will develop flexible low-power neuromorphic μECoG circuits that can detect single
neuron signals from superficial cortical layers of many cortical areas simultaneously. (3) Finally, these novel
technologies will be comprehensively evaluated on a mouse model of obsessive compulsivity and anxiety
using a battery of behavioural tasks to reverse the pathological symptoms (beyond what is achievable by
existing approaches). This project constitutes a major step towards the development and testing of minimallyinvasive
and high-precision technologies for manipulating brain activity patterns, which can impact both our
understanding of the brain and treatment of intractable brain disorders.
Max ERC Funding
1 998 984 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
