Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA TERMESZETTUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BRAINCANNABINOIDS
Project Understanding the molecular blueprint and functional complexity of the endocannabinoid metabolome in the brain
Researcher (PI) István Katona
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Summary
We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.
Max ERC Funding
1 638 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym CholAminCo
Project Synergy and antagonism of cholinergic and dopaminergic systems in associative learning
Researcher (PI) Balazs Gyoergy HANGYA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Summary
Neuromodulators such as acetylcholine and dopamine are able to rapidly reprogram neuronal information processing and dynamically change brain states. Degeneration or dysfunction of cholinergic and dopaminergic neurons can lead to neuropsychiatric conditions like schizophrenia and addiction or cognitive diseases such as Alzheimer’s. Neuromodulatory systems control overlapping cognitive processes and often have similar modes of action; therefore it is important to reveal cooperation and competition between different systems to understand their unique contributions to cognitive functions like learning, memory and attention. This is only possible by direct comparison, which necessitates monitoring multiple neuromodulatory systems under identical experimental conditions. Moreover, simultaneous recording of different neuromodulatory cell types goes beyond phenomenological description of similarities and differences by revealing the underlying correlation structure at the level of action potential timing. However, such data allowing direct comparison of neuromodulatory actions are still sparse. As a first step to bridge this gap, I propose to elucidate the unique versus complementary roles of two “classical” neuromodulatory systems, the cholinergic and dopaminergic projection system implicated in various cognitive functions including associative learning and plasticity. First, we will record optogenetically identified cholinergic and dopaminergic neurons simultaneously using chronic extracellular recording in mice undergoing classical and operant conditioning. Second, we will determine the postsynaptic impact of cholinergic and dopaminergic neurons by manipulating them both separately and simultaneously while recording consequential changes in cortical neuronal activity and learning behaviour. These experiments will reveal how major neuromodulatory systems interact to mediate similar or different aspects of the same cognitive functions.
Max ERC Funding
1 499 463 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym DeCode
Project Dendrites and memory: role of dendritic spikes in information coding by hippocampal CA3 pyramidal neurons
Researcher (PI) Judit MAKARA
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood.
In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks.
The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.
Summary
The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood.
In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks.
The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.
Max ERC Funding
1 990 314 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym FORCEMAP
Project Intramolecular force mapping of enzymes in action: the role of strain in motor mechanisms
Researcher (PI) András Málnási-Csizmadia
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Summary
A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Max ERC Funding
750 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym FRONTHAL
Project Specificity of cortico-thalamic interactions and its role in frontal cortical functions
Researcher (PI) Laszlo ACSADY
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Summary
Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions.
In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes.
The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex.
The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general.
Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.
Max ERC Funding
1 597 575 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym FunctionalProteomics
Project Proteomic fingerprinting of functionally characterized single synapses
Researcher (PI) Zoltan NUSSER
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Advanced Grant (AdG), LS5, ERC-2017-ADG
Summary Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.
Summary
Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.
Max ERC Funding
2 498 750 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym INTERIMPACT
Project Impact of identified interneurons on cellular network mechanisms in the human and rodent neocortex
Researcher (PI) Gábor Tamás
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Summary
This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Max ERC Funding
2 391 695 €
Duration
Start date: 2011-06-01, End date: 2017-05-31
Project acronym MGUS screening RCT
Project Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial
Researcher (PI) Sigurdur Yngvi KRISTINSSON
Host Institution (HI) HASKOLI ISLANDS
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Summary
Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Max ERC Funding
1 474 304 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym MicroCONtACT
Project Microglial control of neuronal activity in the healthy and the injured brain
Researcher (PI) Adam DENES
Host Institution (HI) INSTITUTE OF EXPERIMENTAL MEDICINE - HUNGARIAN ACADEMY OF SCIENCES
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Summary
Microglia are the main immune cells of the brain, but their role in brain injury is highly controversial due to the difficulties in selectively manipulating and imaging microglial actions in real time. Specifically, it is unclear whether microglia control neuronal survival after injury via shaping the activity of complex neuronal networks in vivo. To this end, we have combined fast in vivo two-photon imaging of neuronal calcium responses with selective microglial manipulation for the first time. Our data suggest that microglia constantly monitor and control neuronal network activity and these actions are essential to limit excitotoxicity and neuronal death after acute brain injury. We also identify microglia as key regulators of spreading depolarization in vivo. However, the underlying mechanisms remained unexplored. Here, I propose that microglia control neuronal excitability and based on preliminary data I set out to investigate how this occurs. We will combine selective, CSF1R-mediated microglia depletion with advanced neurophysiological methods such as in vivo calcium imaging and intracranial EEG for the first time, to reveal how microglia shape activity of complex neuronal networks in the healthy and the injured brain. Then, we will study microglia-neuron interactions from the network level to nanoscale level using in vivo two-photon imaging and super-resolution microscopy. We will apply novel chemogenic and optogenetic approaches to manipulate microglia in real time, assess their role in neuronal activity changes and investigate the molecular mechanisms in vitro and in vivo. Our unpublished data also suggest that inflammation – a key contributor to brain diseases – could disrupt microglia-neuron signaling and we set out to investigate the underlying mechanisms. By using state-of the-art research tools that had not been applied previously in this context, our studies are likely to reveal novel pathophysiological mechanisms relevant for common brain diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
