Project acronym AGEMEC
Project Age-dependent mechanisms of sporadic Alzheimer’s Disease in patient-derived neurons
Researcher (PI) Jerome Stefan MERTENS
Host Institution (HI) UNIVERSITAET INNSBRUCK
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Sporadic Alzheimer’s Disease (AD) accounts for the overwhelming majority of all AD cases and exclusively affects people at old age. However, mechanistic links between aging and AD pathology remain elusive. We recently discovered that in contrast to iPSC models, direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of aging, and we have started to develop a patient-based iN model system for AD. Our preliminary data suggests that AD iNs show a neuronal but de-differentiated transcriptome signature. In this project, we first combine cellular neuroscience assays and epigenetic landscape profiling to understand how neurons in AD fail to maintain their fully mature differentiated state, which might be key in permitting disease development. Next, using metabolome analysis including mass spec metabolite assessment, we explore a profound metabolic switch in AD iNs that shows surprisingly many aspects of aerobic glycolysis observed also in cancer. While this link might represent an interesting connection between two age-dependent and de-differentiation-associated diseases, it also opens new avenues to harness knowledge from the cancer field to better understand sporadic AD. We further focus on identifying and manipulating key metabolic regulators that appear to malfunction in an age-dependent manner, with the ultimate goal to define potential targets and treatment strategies. Finally, we will focus on early AD mechanisms by extending our model to mild cognitive impairment (MCI) patients. An agnostic transcriptome and epigenetic landscape approach of glutamatergic and serotonergic iNs will help to determine the earliest and probably most treatable disease mechanisms of AD, and to better understand the contribution of neuropsychiatric risk factors. We anticipate that this project will help to illuminate the mechanistic interface of cellular aging and the development of AD, and help to define new strategies for AD.
Summary
Sporadic Alzheimer’s Disease (AD) accounts for the overwhelming majority of all AD cases and exclusively affects people at old age. However, mechanistic links between aging and AD pathology remain elusive. We recently discovered that in contrast to iPSC models, direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of aging, and we have started to develop a patient-based iN model system for AD. Our preliminary data suggests that AD iNs show a neuronal but de-differentiated transcriptome signature. In this project, we first combine cellular neuroscience assays and epigenetic landscape profiling to understand how neurons in AD fail to maintain their fully mature differentiated state, which might be key in permitting disease development. Next, using metabolome analysis including mass spec metabolite assessment, we explore a profound metabolic switch in AD iNs that shows surprisingly many aspects of aerobic glycolysis observed also in cancer. While this link might represent an interesting connection between two age-dependent and de-differentiation-associated diseases, it also opens new avenues to harness knowledge from the cancer field to better understand sporadic AD. We further focus on identifying and manipulating key metabolic regulators that appear to malfunction in an age-dependent manner, with the ultimate goal to define potential targets and treatment strategies. Finally, we will focus on early AD mechanisms by extending our model to mild cognitive impairment (MCI) patients. An agnostic transcriptome and epigenetic landscape approach of glutamatergic and serotonergic iNs will help to determine the earliest and probably most treatable disease mechanisms of AD, and to better understand the contribution of neuropsychiatric risk factors. We anticipate that this project will help to illuminate the mechanistic interface of cellular aging and the development of AD, and help to define new strategies for AD.
Max ERC Funding
1 499 565 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym AXONENDO
Project Endosomal control of local protein synthesis in axons
Researcher (PI) Jean-Michel Cioni
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.
Summary
Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.
Max ERC Funding
1 499 563 €
Duration
Start date: 2020-09-01, End date: 2025-08-31
Project acronym BehavIndividuality
Project Uncovering the basis of behavioral individuality across developmental time-scales
Researcher (PI) Shay Stern
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary A fundamental question in biology is why different individuals show different behaviors. While individuality in behavior is usually explained by genetic heterogeneity or differences in environmental exposures, more recent studies have shown that stable behavioral variation is also observed among isogenic individuals that were raised in the same environment. However, this important and potentially conserved epigenetic source of individual-to-individual behavioral variation remains largely unexplored. I have recently developed a novel imaging setup, using C. elegans, that allowed for the first time to study behavioral individuality across the full development time of animals, at high spatiotemporal resolution and under tightly controlled environmental conditions (Stern et al. Cell 2017). By using this unique system I found that isogenic animals show long-term behavioral individuality that persists across all developmental stages, and was dependent on specific neuromodulators. In this proposal I suggest to study how behavioral individuality emerges across development from non-genetic differences among individuals. In particular, I plan to (i) identify neuronal circuits and variations therein that lead to different behavioral states among individuals by combining my established methods for longitudinal behavioral quantifications with cutting-edge neuronal imaging and molecular techniques; (ii) study the role of conserved epigenetic mechanisms in generating stable neuronal and behavioral variations by integrating high-throughput gene-expression, neuronal, and behavioral analyses in single animals; and (iii) explore how stressful conditions affect behavioral individuality. I hypothesize that stress may enhance variation as a population-level mechanism to diversify risk in the face of complex or unpredictable conditions. The proposed research will shed light on novel processes that establish and maintain inter-individual diversity in neuronal and behavioral patterns.
Summary
A fundamental question in biology is why different individuals show different behaviors. While individuality in behavior is usually explained by genetic heterogeneity or differences in environmental exposures, more recent studies have shown that stable behavioral variation is also observed among isogenic individuals that were raised in the same environment. However, this important and potentially conserved epigenetic source of individual-to-individual behavioral variation remains largely unexplored. I have recently developed a novel imaging setup, using C. elegans, that allowed for the first time to study behavioral individuality across the full development time of animals, at high spatiotemporal resolution and under tightly controlled environmental conditions (Stern et al. Cell 2017). By using this unique system I found that isogenic animals show long-term behavioral individuality that persists across all developmental stages, and was dependent on specific neuromodulators. In this proposal I suggest to study how behavioral individuality emerges across development from non-genetic differences among individuals. In particular, I plan to (i) identify neuronal circuits and variations therein that lead to different behavioral states among individuals by combining my established methods for longitudinal behavioral quantifications with cutting-edge neuronal imaging and molecular techniques; (ii) study the role of conserved epigenetic mechanisms in generating stable neuronal and behavioral variations by integrating high-throughput gene-expression, neuronal, and behavioral analyses in single animals; and (iii) explore how stressful conditions affect behavioral individuality. I hypothesize that stress may enhance variation as a population-level mechanism to diversify risk in the face of complex or unpredictable conditions. The proposed research will shed light on novel processes that establish and maintain inter-individual diversity in neuronal and behavioral patterns.
Max ERC Funding
1 375 000 €
Duration
Start date: 2019-12-01, End date: 2024-11-30
Project acronym CELPRED
Project Circuit elements of the cortical circuit for predictive processing
Researcher (PI) Georg KELLER
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Summary
One promising theoretical framework to explain the function of cortex is predictive processing. It postulates that cortex functions by maintaining an internal model, or internal representation, of the world through a comparison of predictions based on this internal model with incoming sensory information. Implementing predictive processing in a cortical circuit would require a set of distinct functional cell types. These would include neurons that compute a difference between top-down predictions and bottom-up input, referred to as prediction error neurons, and a separate population of neurons that integrate the output of prediction error neurons to maintain an internal representation of the world. This research proposal will test the framework of predictive processing and identify different putative circuit elements and cell types that are thought to form the circuit in mouse visual cortex. We will use a combination of physiological recordings, optogenetic manipulations of neural activity, and gene expression measurements to determine the cell types that have functional responses consistent with different prediction errors, as well as those coding for the internal representation. Identifying the circuit elements underlying predictive processing in cortex may reveal a strategy to bias processing either towards top-down or bottom-up drive when the balance between the two is perturbed, as may be the case in neuropsychiatric disorders.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym CLAUSTRUM
Project Optical interrogation of the claustrum from synapses to behavior
Researcher (PI) Adam Max PACKER
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary How does the brain integrate inputs from the environment to generate perception and drive decisions? An enigmatic brain region called the claustrum has been suggested to play a role by integrating inputs from multiple brain regions. There is strong interconnectivity between claustrum and nearly every neocortical brain region, indicating that it exerts widespread influence on brain function. However, approaches to specifically record from or manipulate activity in the claustrum have been hindered by the inability to target it selectively. This has been difficult due to the anatomy of the claustrum: it is a long, thin bilateral nucleus buried between the neocortex and the striatum. This proposal aims to understand the role of the claustrum in multisensory integration and behaviour by developing new approaches for monitoring and manipulating the activity of the claustrum. We will harness recent advances in electrophysiological, genetic, optical, and behavioural tools to probe its connectivity, activity, and function in a precise manner. Understanding the role of the claustrum in brain function will provide fundamental insight into information processing in the neocortex, which is a major goal in neuroscience. The claustrum is unique because of its dense reciprocal connectivity with neocortex but nearly complete lack of direct subcortical sensory input. This particular anatomical structure indicates the possibility of a unique function, but none has been observed yet. This proposal will rectify the paucity of data on this distinctive structure by applying a battery of modern tools to address the function of the claustrum. Experiments will address the following key questions:
1. How are claustrocortical inputs integrated and what is the effect of corticoclaustral feedback?
2. What is the activity of claustral neurons during sensory stimulation and motor output?
3. What are the causal relationships between claustrum activity and animal behaviour?
Summary
How does the brain integrate inputs from the environment to generate perception and drive decisions? An enigmatic brain region called the claustrum has been suggested to play a role by integrating inputs from multiple brain regions. There is strong interconnectivity between claustrum and nearly every neocortical brain region, indicating that it exerts widespread influence on brain function. However, approaches to specifically record from or manipulate activity in the claustrum have been hindered by the inability to target it selectively. This has been difficult due to the anatomy of the claustrum: it is a long, thin bilateral nucleus buried between the neocortex and the striatum. This proposal aims to understand the role of the claustrum in multisensory integration and behaviour by developing new approaches for monitoring and manipulating the activity of the claustrum. We will harness recent advances in electrophysiological, genetic, optical, and behavioural tools to probe its connectivity, activity, and function in a precise manner. Understanding the role of the claustrum in brain function will provide fundamental insight into information processing in the neocortex, which is a major goal in neuroscience. The claustrum is unique because of its dense reciprocal connectivity with neocortex but nearly complete lack of direct subcortical sensory input. This particular anatomical structure indicates the possibility of a unique function, but none has been observed yet. This proposal will rectify the paucity of data on this distinctive structure by applying a battery of modern tools to address the function of the claustrum. Experiments will address the following key questions:
1. How are claustrocortical inputs integrated and what is the effect of corticoclaustral feedback?
2. What is the activity of claustral neurons during sensory stimulation and motor output?
3. What are the causal relationships between claustrum activity and animal behaviour?
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym CN Identity
Project Comprehensive anatomical, genetic and functional identification of cerebellar nuclei neurons and their roles in sensorimotor tasks
Researcher (PI) Zhenyu Gao
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary How does the brain integrate diverse sensory inputs and generate appropriate motor commands? Our cerebellum is a key region for such a sensorimotor processing, empowered by its sophisticated neural computation and constant communication with other brain regions. The well-timed cerebellar information is integrated and funneled to other brain regions through the cerebellar nuclei (CN). Yet, how CN circuitry contributes to the cerebellar control of sensorimotor processing is unclear. My recent work indicates that the CN activity serves various functions ranging from the online motor control, the amplitude amplification of cerebellar outputs to the control of motor planning. Given these advances, I am now in a unique position to decipher the properties of CN neurons and identify their specific roles in different forms of sensorimotor processing. It is my central hypothesis that depending on the specific demands of the task, CN neurons can either facilitate or suppress the activity of downstream regions with millisecond precision; and the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this hypothesis, I will 1) identify the activity patterns of different CN modules during the acquisition and execution of two sensorimotor tasks and characterize the relevant extra-cerebellar inputs to these modules; 2) identify the connectivity-transcription logic of different CN modules and link them to their task-specific outputs; and 3) examine the impacts of manipulating anatomically and/or genetically defined CN neurons on the downstream regions during different sensorimotor tasks. I will accomplish these key objectives by developing various novel electrophysiological, optogenetic, molecular and imaging techniques. My research is likely to break new ground, demonstrating that the identity of CN neurons is determined by their differential temporal demands of sensorimotor tasks controlled by different brain structures.
Summary
How does the brain integrate diverse sensory inputs and generate appropriate motor commands? Our cerebellum is a key region for such a sensorimotor processing, empowered by its sophisticated neural computation and constant communication with other brain regions. The well-timed cerebellar information is integrated and funneled to other brain regions through the cerebellar nuclei (CN). Yet, how CN circuitry contributes to the cerebellar control of sensorimotor processing is unclear. My recent work indicates that the CN activity serves various functions ranging from the online motor control, the amplitude amplification of cerebellar outputs to the control of motor planning. Given these advances, I am now in a unique position to decipher the properties of CN neurons and identify their specific roles in different forms of sensorimotor processing. It is my central hypothesis that depending on the specific demands of the task, CN neurons can either facilitate or suppress the activity of downstream regions with millisecond precision; and the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this hypothesis, I will 1) identify the activity patterns of different CN modules during the acquisition and execution of two sensorimotor tasks and characterize the relevant extra-cerebellar inputs to these modules; 2) identify the connectivity-transcription logic of different CN modules and link them to their task-specific outputs; and 3) examine the impacts of manipulating anatomically and/or genetically defined CN neurons on the downstream regions during different sensorimotor tasks. I will accomplish these key objectives by developing various novel electrophysiological, optogenetic, molecular and imaging techniques. My research is likely to break new ground, demonstrating that the identity of CN neurons is determined by their differential temporal demands of sensorimotor tasks controlled by different brain structures.
Max ERC Funding
1 400 000 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym DimorphicCircuits
Project Elucidating the development of sexually-dimorphic circuits: from molecular mechanisms to synapses and behavior
Researcher (PI) Meital Oren-Suissa
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary In sexually reproducing species, males and females respond to environmental sensory cues and transform the input into sexually dimorphic traits. These dimorphisms are the basis for sex-biased phenotypes in many neurological diseases. Yet, complete understanding of the underlying mechanism is still missing. How does the sexual identity impose molecular changes to individual neurons and circuits? What are the sex-specific synaptic changes that occur during development in these circuits? We recently demonstrated a sexually dimorphic dimension of neuronal connectivity: neurons belonging to a shared nervous system rewire in a sex-specific manner to generate sexually dimorphic behaviors. New findings from our lab further reveal a significant difference in the way the two sexes in the nematode C. elegans respond to aversive stimuli. These dimorphic responses are mediated via sex-shared circuits that receive similar environmental input, yet respond differently.
Building on our exciting preliminary results, we seek to elucidate how genetic sex modulates neuronal function, neural circuit dynamics and behavior during development. This proposal will pursue three complementary objectives: (i) Map the repertoire of sexually dimorphic avoidance behaviors; (ii) Study the synaptic basis for the development of sexually dimorphic circuits; and (iii) Elucidate the molecular basis of sexually dimorphic neuronal circuits. These mechanisms can only be currently resolved in C. elegans, where the entire connectome of the nervous system for both sexes has been mapped. Using cutting-edge optogenetics, calcium imaging, activity-dependent trans-synaptic labeling, genetic screens and single-cell transcriptome analysis we will shed light on the elusive connection between genes, circuits and behavior. Understanding how genetic sex modulates neuronal circuits will aid in the development of novel gender-specific therapies.
Summary
In sexually reproducing species, males and females respond to environmental sensory cues and transform the input into sexually dimorphic traits. These dimorphisms are the basis for sex-biased phenotypes in many neurological diseases. Yet, complete understanding of the underlying mechanism is still missing. How does the sexual identity impose molecular changes to individual neurons and circuits? What are the sex-specific synaptic changes that occur during development in these circuits? We recently demonstrated a sexually dimorphic dimension of neuronal connectivity: neurons belonging to a shared nervous system rewire in a sex-specific manner to generate sexually dimorphic behaviors. New findings from our lab further reveal a significant difference in the way the two sexes in the nematode C. elegans respond to aversive stimuli. These dimorphic responses are mediated via sex-shared circuits that receive similar environmental input, yet respond differently.
Building on our exciting preliminary results, we seek to elucidate how genetic sex modulates neuronal function, neural circuit dynamics and behavior during development. This proposal will pursue three complementary objectives: (i) Map the repertoire of sexually dimorphic avoidance behaviors; (ii) Study the synaptic basis for the development of sexually dimorphic circuits; and (iii) Elucidate the molecular basis of sexually dimorphic neuronal circuits. These mechanisms can only be currently resolved in C. elegans, where the entire connectome of the nervous system for both sexes has been mapped. Using cutting-edge optogenetics, calcium imaging, activity-dependent trans-synaptic labeling, genetic screens and single-cell transcriptome analysis we will shed light on the elusive connection between genes, circuits and behavior. Understanding how genetic sex modulates neuronal circuits will aid in the development of novel gender-specific therapies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ExpectBG
Project Elucidating the Basal Ganglia Circuits for Reward Expectation
Researcher (PI) Marcus Stephenson-Jones
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Predicting future outcomes is fundamental for adaptive behaviour. Reward-predicting stimuli evoke a state of expectation, which informs motivation, guides attention, and drives preparatory motor behaviour. Reward expectations are crucial for learning since they serve as a comparison to actual outcomes. This comparison allows animals to determine if there is a prediction error (i.e. if an outcome was better or worse than expected). Even though reward expectation signals are observed in many areas of the brain how they are computed remains unknown. The main reason for lack of progress is the absence of a clear understanding of where expectation is generated and which circuits are involved in its computation. Consequently, we are missing the prerequisite knowledge for determining where reward expectation arises, how it is computed, and how expectations are learnt. We hypothesize, based on preliminary data and prior literature, that specific circuits within the basal ganglia are crucial for computing reward expectation. We will utilize cutting edge viral methods, combined with electrophysiological recordings and calcium imaging techniques, to identify the specific circuits and cell-types within the basal ganglia nuclei that compute reward expectation. The causal role these identified circuits play in learning will be determined using cell-type specific manipulations in mice performing reinforcement learning tasks. Finally, we will pioneer approaches to manipulate elements of the basal ganglia circuit, while simultaneously recording from specific cell types in the ventral tegmental area, that are involved in computing reward prediction error. Together, this work will uncover how specific basal ganglia cell types causally contribute to the computation of reward expectation and the calculation of reward prediction error. This will provide a foundation for understating how reward expectation influences adaptive behaviour and is perturbed in psychiatric disease.
Summary
Predicting future outcomes is fundamental for adaptive behaviour. Reward-predicting stimuli evoke a state of expectation, which informs motivation, guides attention, and drives preparatory motor behaviour. Reward expectations are crucial for learning since they serve as a comparison to actual outcomes. This comparison allows animals to determine if there is a prediction error (i.e. if an outcome was better or worse than expected). Even though reward expectation signals are observed in many areas of the brain how they are computed remains unknown. The main reason for lack of progress is the absence of a clear understanding of where expectation is generated and which circuits are involved in its computation. Consequently, we are missing the prerequisite knowledge for determining where reward expectation arises, how it is computed, and how expectations are learnt. We hypothesize, based on preliminary data and prior literature, that specific circuits within the basal ganglia are crucial for computing reward expectation. We will utilize cutting edge viral methods, combined with electrophysiological recordings and calcium imaging techniques, to identify the specific circuits and cell-types within the basal ganglia nuclei that compute reward expectation. The causal role these identified circuits play in learning will be determined using cell-type specific manipulations in mice performing reinforcement learning tasks. Finally, we will pioneer approaches to manipulate elements of the basal ganglia circuit, while simultaneously recording from specific cell types in the ventral tegmental area, that are involved in computing reward prediction error. Together, this work will uncover how specific basal ganglia cell types causally contribute to the computation of reward expectation and the calculation of reward prediction error. This will provide a foundation for understating how reward expectation influences adaptive behaviour and is perturbed in psychiatric disease.
Max ERC Funding
1 498 100 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym GliomaSignals
Project Oncometabolitic control of tumor growth and epileptogenesis in IDH mutated gliomas: D2HG signaling mechanism.
Researcher (PI) Gilles Huberfeld
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary Dysregulated growth processes of gliomas interact with pro-epileptic plasticity of brain circuits in such a way that the excitatory transmitter glutamate promotes autocrine tumor invasion as well as epileptic synchrony in surrounding cortical regions. Most low-grade gliomas are associated with mutations of Isocitrate DesHydrogenase (IDH) genes which lead to an excess of the oncometabolite D-2-Hydroxyglutarate (D2HG). With a structure mimicking glutamate, D2HG is thought to participate in both epileptogenic and oncologic processes. Importantly, while epileptic activity is accentuated, tumor prognosis is improved in affected people. My preliminary data now suggest a dual function for D2HG, acting as a glutamatergic agonist at high levels, but as an antagonist in the presence of glutamate. Solving this paradox will be a step forward in glioma science. The GliomasSignals project will examine the role of D2HG in the neurobiology of gliomas bringing electrophysiology concepts and tools to neuro-oncology, seeking to transform our understanding. It seeks to better understand how D2HG modulates glutamatergic signaling, affects neuronal excitability and tumor growth, and to detect the extent to which tumor infiltration colocalizes with epileptic remodeling. In vivo and in vitro work mostly on human tissue will aim at: 1- Map biomarkers of epileptic activity / tumor infiltration by cortical recordings during surgery using unique next generation Neurogrid electrodes. 2- Correlate D2HG levels, glutamate concentrations and tumor infiltration with recordings in peritumoral cortex at an unprecedented resolution. 3- Identify D2HG effects on glutamate signaling in human tissue slices producing epileptic activities and in a rodent model. 4- Explore D2HG long-term effects on epileptic activity and tumor growth / infiltration in co-cultures of tumors with surrounding peritumoral cortex by exploiting our unique capabilities for long-term human cortex organotypic cultures.
Summary
Dysregulated growth processes of gliomas interact with pro-epileptic plasticity of brain circuits in such a way that the excitatory transmitter glutamate promotes autocrine tumor invasion as well as epileptic synchrony in surrounding cortical regions. Most low-grade gliomas are associated with mutations of Isocitrate DesHydrogenase (IDH) genes which lead to an excess of the oncometabolite D-2-Hydroxyglutarate (D2HG). With a structure mimicking glutamate, D2HG is thought to participate in both epileptogenic and oncologic processes. Importantly, while epileptic activity is accentuated, tumor prognosis is improved in affected people. My preliminary data now suggest a dual function for D2HG, acting as a glutamatergic agonist at high levels, but as an antagonist in the presence of glutamate. Solving this paradox will be a step forward in glioma science. The GliomasSignals project will examine the role of D2HG in the neurobiology of gliomas bringing electrophysiology concepts and tools to neuro-oncology, seeking to transform our understanding. It seeks to better understand how D2HG modulates glutamatergic signaling, affects neuronal excitability and tumor growth, and to detect the extent to which tumor infiltration colocalizes with epileptic remodeling. In vivo and in vitro work mostly on human tissue will aim at: 1- Map biomarkers of epileptic activity / tumor infiltration by cortical recordings during surgery using unique next generation Neurogrid electrodes. 2- Correlate D2HG levels, glutamate concentrations and tumor infiltration with recordings in peritumoral cortex at an unprecedented resolution. 3- Identify D2HG effects on glutamate signaling in human tissue slices producing epileptic activities and in a rodent model. 4- Explore D2HG long-term effects on epileptic activity and tumor growth / infiltration in co-cultures of tumors with surrounding peritumoral cortex by exploiting our unique capabilities for long-term human cortex organotypic cultures.
Max ERC Funding
1 875 135 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym H I C I
Project Transcriptional and epigenetic control of tissue regenerative HB-EGF in autoimmune CNS inflammation
Researcher (PI) Veit Johannes Rothhammer
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS), in which chronic inflammation and failure of regenerative mechanisms lead to progressive tissue destruction and accumulation of neurological deficits. Glial cells such as astrocytes induce regenerative processes in acute inflammation, but fail to inhibit tissue destruction for yet unknown reasons in chronic disease. In preliminary studies, we identified heparin-binding EGF-like growth factor (HB-EGF) in astrocytes as novel tissue protective factor. Indeed, knock-down of HB-EGF in astrocytes led to exacerbated disease and failure to recover in an animal model of MS. Promoter studies revealed induction of HB-EGF by the ligand-induced transcription factor aryl hydrocarbon receptor (AHR) in acute inflammation. However, astrocytic HB-EGF decreased in chronic stages concomitantly with progressive disease worsening. Analyses of AHR binding sites in the HB-EGF promoter revealed epigenetic modifications mediated by DNA-Methyltransferase 1 (DNMT1) in chronic inflammation, which inhibited promoter activation by AHR. Knocking down DNMT1 prevented epigenetic changes and increased HB-EGF production in chronic stages. Thus, we have discovered astrocytic HB-EGF as a novel regenerative factor and its regulation by AHR and DNMT1, which could be targeted therapeutically to enhance tissue regeneration in chronic stages. In this project, we will define the role of HB-EGF in acute and chronic autoimmune CNS inflammation (Aim 1), its regulation by AHR and DNMT1 (Aim 2), and the therapeutic value of nasal HB-EGF application or DNMT1 blockade (Aim 3). In a translational approach, we will validate AHR ligands, HB-EGF and HB-EGF promoter methylation status in serum and cerebrospinal fluid of MS patients as novel biomarkers for MS (Aim 4). These high risk/high gain studies explore novel concepts for monitoring and therapy of yet untreatable stages of MS and other degenerative diseases of the CNS.
Summary
Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS), in which chronic inflammation and failure of regenerative mechanisms lead to progressive tissue destruction and accumulation of neurological deficits. Glial cells such as astrocytes induce regenerative processes in acute inflammation, but fail to inhibit tissue destruction for yet unknown reasons in chronic disease. In preliminary studies, we identified heparin-binding EGF-like growth factor (HB-EGF) in astrocytes as novel tissue protective factor. Indeed, knock-down of HB-EGF in astrocytes led to exacerbated disease and failure to recover in an animal model of MS. Promoter studies revealed induction of HB-EGF by the ligand-induced transcription factor aryl hydrocarbon receptor (AHR) in acute inflammation. However, astrocytic HB-EGF decreased in chronic stages concomitantly with progressive disease worsening. Analyses of AHR binding sites in the HB-EGF promoter revealed epigenetic modifications mediated by DNA-Methyltransferase 1 (DNMT1) in chronic inflammation, which inhibited promoter activation by AHR. Knocking down DNMT1 prevented epigenetic changes and increased HB-EGF production in chronic stages. Thus, we have discovered astrocytic HB-EGF as a novel regenerative factor and its regulation by AHR and DNMT1, which could be targeted therapeutically to enhance tissue regeneration in chronic stages. In this project, we will define the role of HB-EGF in acute and chronic autoimmune CNS inflammation (Aim 1), its regulation by AHR and DNMT1 (Aim 2), and the therapeutic value of nasal HB-EGF application or DNMT1 blockade (Aim 3). In a translational approach, we will validate AHR ligands, HB-EGF and HB-EGF promoter methylation status in serum and cerebrospinal fluid of MS patients as novel biomarkers for MS (Aim 4). These high risk/high gain studies explore novel concepts for monitoring and therapy of yet untreatable stages of MS and other degenerative diseases of the CNS.
Max ERC Funding
1 499 706 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
