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 NETWORK EVOLUTION
Project Integrated evolutionary analyses of genetic and drug interaction networks in yeast
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Summary
The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Max ERC Funding
1 280 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym OscillInterference
Project Therapeutic Mechanisms and Long Term Effects of Directed Transcranial Alternating Current Stimulation in Epileptic Seizures
Researcher (PI) Antal Berényi
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Summary
A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Max ERC Funding
1 419 000 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym OSSMA
Project Multiple Systems of Spatial Memory: Their role in Reasoning and Action
Researcher (PI) Marios Avraamides
Host Institution (HI) UNIVERSITY OF CYPRUS
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary The goal of the proposed project is to examine how the locations of the objects that constitute our environments are represented in memory and how such memories are used to support our actions in space. During the last three decades of research this topic has received a lot of attention by scientists from many disciplines, and over the years a number of theories have been formulated. However, our understanding of the nature and functioning of spatial memory still continues to change. More importantly, there exist empirical findings from two concentrations of research within spatial cognition that seem conflicting at first glance. On one hand, studies examining the organizational structure of spatial memory have shown that memories are encoded using allocentric reference frames; that is reference frames that encode the spatial relations among the objects of an environment. On the other hand, studies focusing on how people stay oriented towards their surroundings during locomotion suggest that egocentric representations (i.e., representations coding self-to-object relations) are involved. Recent models of spatial cognition have attempted to reconcile these findings by proposing multiple systems for spatial memory. In this project we will carry our a series of experiments in an attempt to gather empirical data to test the predictions of various theoretical models including a biologically-plausible two-system account of spatial memory that we have recently proposed (Avraamides & Kelly, in press). Drawing heavily from the literature on Stimulus-Response compatibility, this account combines the use of egocentric and allocentric representations to account for a wealth of data from all areas of spatial cognition.
Summary
The goal of the proposed project is to examine how the locations of the objects that constitute our environments are represented in memory and how such memories are used to support our actions in space. During the last three decades of research this topic has received a lot of attention by scientists from many disciplines, and over the years a number of theories have been formulated. However, our understanding of the nature and functioning of spatial memory still continues to change. More importantly, there exist empirical findings from two concentrations of research within spatial cognition that seem conflicting at first glance. On one hand, studies examining the organizational structure of spatial memory have shown that memories are encoded using allocentric reference frames; that is reference frames that encode the spatial relations among the objects of an environment. On the other hand, studies focusing on how people stay oriented towards their surroundings during locomotion suggest that egocentric representations (i.e., representations coding self-to-object relations) are involved. Recent models of spatial cognition have attempted to reconcile these findings by proposing multiple systems for spatial memory. In this project we will carry our a series of experiments in an attempt to gather empirical data to test the predictions of various theoretical models including a biologically-plausible two-system account of spatial memory that we have recently proposed (Avraamides & Kelly, in press). Drawing heavily from the literature on Stimulus-Response compatibility, this account combines the use of egocentric and allocentric representations to account for a wealth of data from all areas of spatial cognition.
Max ERC Funding
500 000 €
Duration
Start date: 2008-10-01, End date: 2013-06-30
