Project acronym ADDICTIONCIRCUITS
Project Drug addiction: molecular changes in reward and aversion circuits
Researcher (PI) Nils David Engblom
Host Institution (HI) LINKOPINGS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Summary
Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym AfricanNeo
Project The African Neolithic: A genetic perspective
Researcher (PI) Carina SCHLEBUSCH
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), SH6, ERC-2017-STG
Summary The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Summary
The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym AFRODITE
Project Advanced Fluid Research On Drag reduction In Turbulence Experiments
Researcher (PI) Jens Henrik Mikael Fransson
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Country Sweden
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.
Summary
A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.
Max ERC Funding
1 418 399 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym BRAINCELL
Project Charting the landscape of brain development by large-scale single-cell transcriptomics and phylogenetic lineage reconstruction
Researcher (PI) Sten Linnarsson
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Embryogenesis is the temporal unfolding of cellular processes: proliferation, migration, differentiation, morphogenesis, apoptosis and functional specialization. These processes are well understood in specific tissues, and for specific cell types. Nevertheless, our systematic knowledge of the types of cells present in the developing and adult animal, and about their functional and lineage relationships, is limited. For example, there is no consensus on the number of cell types, and many important stem cells and progenitors remain to be discovered. Similarly, the lineage relationships between specific cell types are often poorly characterized. This is particularly true for the mammalian nervous system. We have developed (1) a reliable high-throghput method for sequencing all transcripts in 96 single cells at a time; and (2) a system for high-throughput phylogenetic lineage reconstruction. We now propose to characterize embryogenesis using a shotgun approach borrowed from genomics. Tissues will be dissected from multiple stages and dissociated to single cells. A total of 10,000 cells will be analyzed by RNA sequencing, revealing their functional cell type, their lineage relationships, and their current state (e.g. cell cycle phase). The novel approach proposed here will bring the powerful strategies pioneered in genomics into the field of developmental biology, including automation, digitization, and the random shotgun method. The data thus obtained will bring clarity to the concept of ‘cell type’; will provide a first catalog of mouse brain cell types with deep functional annotation; will provide markers for every cell type, including stem cells; and will serve as a basis for future comparative work, especially with human embryos.
Summary
Embryogenesis is the temporal unfolding of cellular processes: proliferation, migration, differentiation, morphogenesis, apoptosis and functional specialization. These processes are well understood in specific tissues, and for specific cell types. Nevertheless, our systematic knowledge of the types of cells present in the developing and adult animal, and about their functional and lineage relationships, is limited. For example, there is no consensus on the number of cell types, and many important stem cells and progenitors remain to be discovered. Similarly, the lineage relationships between specific cell types are often poorly characterized. This is particularly true for the mammalian nervous system. We have developed (1) a reliable high-throghput method for sequencing all transcripts in 96 single cells at a time; and (2) a system for high-throughput phylogenetic lineage reconstruction. We now propose to characterize embryogenesis using a shotgun approach borrowed from genomics. Tissues will be dissected from multiple stages and dissociated to single cells. A total of 10,000 cells will be analyzed by RNA sequencing, revealing their functional cell type, their lineage relationships, and their current state (e.g. cell cycle phase). The novel approach proposed here will bring the powerful strategies pioneered in genomics into the field of developmental biology, including automation, digitization, and the random shotgun method. The data thus obtained will bring clarity to the concept of ‘cell type’; will provide a first catalog of mouse brain cell types with deep functional annotation; will provide markers for every cell type, including stem cells; and will serve as a basis for future comparative work, especially with human embryos.
Max ERC Funding
1 496 032 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym CEV
Project Coordination by Evaluations and Valuations:
Market Logic Inside and Outside the Economy
Researcher (PI) Jonas Patrik Aspers
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), SH2, ERC-2010-StG_20091209
Summary This project studies evaluation and valuation as ways of coordinating actors and resources. Valuation is the ascribing of value to people, organizations, things and events given that there is no standard of value. Evaluation is judging according to an already existing value-standard. Valuation and evaluation are ways of ranking and thus ordering of objects . Markets are examples of economic social formations in which valuations and evaluations are the foundation for the choices made. Valuation and evaluation are important means of coordination also outside of the economy, in competitions (e.g., sports), reviews (e.g., books), and auditing (e.g., of ethical conduct).
This project is motivated by evaluation and valuation as increasingly influential ways of coordinating social life. Choices based on evaluation have gradually replaced networks and hierarchies as the preferred coordination form, but processes of valuation or evaluation are not well-understood. The overarching research question of this project is: how do processes of coordination based on valuations function? By understanding these processes can we analyze the consequences of coordinated by the means of evaluation in different spheres of life. It is also the foundation for policy suggestions.
The proposed project uses theoretical insights about market elements in economics and sociology and on the relational sociological literature on social formations. Empirical sub-projects are designed to facilitate comparison, to establish validated conclusions and to promote theory development. This project opens up a new avenue of research of coordination based on valuation and evaluation. It will lead to the establishment a high quality research group located at the frontiers of social science.
Summary
This project studies evaluation and valuation as ways of coordinating actors and resources. Valuation is the ascribing of value to people, organizations, things and events given that there is no standard of value. Evaluation is judging according to an already existing value-standard. Valuation and evaluation are ways of ranking and thus ordering of objects . Markets are examples of economic social formations in which valuations and evaluations are the foundation for the choices made. Valuation and evaluation are important means of coordination also outside of the economy, in competitions (e.g., sports), reviews (e.g., books), and auditing (e.g., of ethical conduct).
This project is motivated by evaluation and valuation as increasingly influential ways of coordinating social life. Choices based on evaluation have gradually replaced networks and hierarchies as the preferred coordination form, but processes of valuation or evaluation are not well-understood. The overarching research question of this project is: how do processes of coordination based on valuations function? By understanding these processes can we analyze the consequences of coordinated by the means of evaluation in different spheres of life. It is also the foundation for policy suggestions.
The proposed project uses theoretical insights about market elements in economics and sociology and on the relational sociological literature on social formations. Empirical sub-projects are designed to facilitate comparison, to establish validated conclusions and to promote theory development. This project opens up a new avenue of research of coordination based on valuation and evaluation. It will lead to the establishment a high quality research group located at the frontiers of social science.
Max ERC Funding
1 476 251 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
Project acronym collectiveQCD
Project Collectivity in small, srongly interacting systems
Researcher (PI) Korinna ZAPP
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), PE2, ERC-2018-STG
Summary In collisions of heavy nuclei at collider energies, for instance at the Large Hadron Collider (LHC) at CERN, the energy density is so high that an equilibrated Quark-Gluon Plasma (QGP), an exotic state of matter consisting of deconfined quarks and gluons, is formed. In proton-proton (p+p) collisions, on the other hand, the density of produced particles is low. The traditional view on such reactions is that final state particles are free and do not rescatter. This picture is challenged by recent LHC data, which found features in p+p collisions that are indicative of collective behaviour and/or the formation of a hot and dense system. These findings have been taken as signs of QGP formation in p+p reactions. Such an interpretation is complicated by the fact that jets, which are the manifestation of very energetic quarks and gluons, are quenched in heavy ion collisions, but appear to be unmodified in p+p reactions. This is puzzling because collectivity and jet quenching are caused by the same processes. So far there is no consensus about the interpretation of these results, which is also due to a lack of suitable tools.
It is the objective of this proposal to address the question whether there are collective effects in p+p collisions. To this end two models capable of describing all relevant aspects of p+p and heavy ion collisions will be developed. They will be obtained by extending a successful description of p+p to heavy ion reactions and vice versa.
The answer to these questions will either clarify the long-standing problem how collectivity emerges from fundamental interactions, or it will necessitate qualitative changes to our interpretation of collective phenomena in p+p and/or heavy ion collisions.
The PI is in a unique position to accomplish this goal, as she has spent her entire career working on different aspects of p+p and heavy ion collisions. The group in Lund is the ideal host, as it is very active in developing alternative interpretations of the data.
Summary
In collisions of heavy nuclei at collider energies, for instance at the Large Hadron Collider (LHC) at CERN, the energy density is so high that an equilibrated Quark-Gluon Plasma (QGP), an exotic state of matter consisting of deconfined quarks and gluons, is formed. In proton-proton (p+p) collisions, on the other hand, the density of produced particles is low. The traditional view on such reactions is that final state particles are free and do not rescatter. This picture is challenged by recent LHC data, which found features in p+p collisions that are indicative of collective behaviour and/or the formation of a hot and dense system. These findings have been taken as signs of QGP formation in p+p reactions. Such an interpretation is complicated by the fact that jets, which are the manifestation of very energetic quarks and gluons, are quenched in heavy ion collisions, but appear to be unmodified in p+p reactions. This is puzzling because collectivity and jet quenching are caused by the same processes. So far there is no consensus about the interpretation of these results, which is also due to a lack of suitable tools.
It is the objective of this proposal to address the question whether there are collective effects in p+p collisions. To this end two models capable of describing all relevant aspects of p+p and heavy ion collisions will be developed. They will be obtained by extending a successful description of p+p to heavy ion reactions and vice versa.
The answer to these questions will either clarify the long-standing problem how collectivity emerges from fundamental interactions, or it will necessitate qualitative changes to our interpretation of collective phenomena in p+p and/or heavy ion collisions.
The PI is in a unique position to accomplish this goal, as she has spent her entire career working on different aspects of p+p and heavy ion collisions. The group in Lund is the ideal host, as it is very active in developing alternative interpretations of the data.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym COOPNET
Project Cooperative Situational Awareness for Wireless Networks
Researcher (PI) Henk Wymeersch
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Country Sweden
Call Details Starting Grant (StG), PE7, ERC-2010-StG_20091028
Summary Devices in wireless networks are no longer used only for communicating binary information, but also for navigation and to sense their surroundings. We are currently approaching fundamental limitations in terms of communication throughput, position information availability and accuracy, and decision making based on sensory data. The goal of this proposal is to understand how the cooperative nature of future wireless networks can be leveraged to perform timekeeping, positioning, communication, and decision making, so as to obtain orders of magnitude performance improvements compared to current architectures.
Our research will have implications in many fields and will comprise fundamental theoretical contributions as well as a cooperative wireless testbed. The fundamental contributions will lead to a deep understanding of cooperative wireless networks and will enable new pervasive applications which currently cannot be supported. The testbed will be used to validate the research, and will serve as a kernel for other researchers worldwide to advance knowledge on cooperative networks. Our work will build on and consolidate knowledge currently dispersed in different scientific disciplines and communities (such as communication theory, sensor networks, distributed estimation and detection, environmental monitoring, control theory, positioning and timekeeping, distributed optimization). It will give a new thrust to research within those communities and forge relations between them.
Summary
Devices in wireless networks are no longer used only for communicating binary information, but also for navigation and to sense their surroundings. We are currently approaching fundamental limitations in terms of communication throughput, position information availability and accuracy, and decision making based on sensory data. The goal of this proposal is to understand how the cooperative nature of future wireless networks can be leveraged to perform timekeeping, positioning, communication, and decision making, so as to obtain orders of magnitude performance improvements compared to current architectures.
Our research will have implications in many fields and will comprise fundamental theoretical contributions as well as a cooperative wireless testbed. The fundamental contributions will lead to a deep understanding of cooperative wireless networks and will enable new pervasive applications which currently cannot be supported. The testbed will be used to validate the research, and will serve as a kernel for other researchers worldwide to advance knowledge on cooperative networks. Our work will build on and consolidate knowledge currently dispersed in different scientific disciplines and communities (such as communication theory, sensor networks, distributed estimation and detection, environmental monitoring, control theory, positioning and timekeeping, distributed optimization). It will give a new thrust to research within those communities and forge relations between them.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym ELECTRONOPERA
Project Electron dynamics to the Attosecond time scale and Angstrom length scale on low dimensional structures in Operation
Researcher (PI) Anders Mikkelsen
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Starting Grant (StG), PE3, ERC-2010-StG_20091028
Summary We will develop and use imaging techniques for direct probing of electron dynamics in low dimensional structures with orders of
magnitude improvements in time and spatial resolution. We will perform our measurements not only on static structures, but on
complex structures under operating conditions. Finally as our equipment can also probe structural properties from microns to
single atom defects we can directly correlate our observations of electron dynamics with knowledge of geometrical structure. We
hope to directly answer central questions in nanophysics on how complex geometric structure on several length-scales induces
new and surprising electron dynamics and thus properties in nanoscale objects.
The low dimensional semiconductors and metal (nano) structures studied will be chosen to have unique novel properties that will
have potential applications in IT, life-science and renewable energy.
To radically increase our diagnostics capabilities we will combine PhotoEmission Electron Microscopy and attosecond XUV/IR
laser technology to directly image surface electron dynamics with attosecond time resolution and nanometer lateral resolution.
Exploring a completely new realm in terms of timescale with nm resolution we will start with rather simple structure such as Au
nanoparticles and arrays nanoholes in ultrathin metal films, and gradually increase complexity.
As the first group in the world we have shown that atomic resolved structural and electrical measurements by Scanning Tunneling
Microscopy is possible on complex 1D semiconductors heterostructures. Importantly, our new method allows for direct studies of
nanowires in devices.
We can now measure atomic scale surface chemistry and surface electronic/geometric structure directly on operational/operating
nanoscale devices. This is important both from a technology point of view, and is an excellent playground for understanding the
fundamental interplay between electronic and structural properties.
Summary
We will develop and use imaging techniques for direct probing of electron dynamics in low dimensional structures with orders of
magnitude improvements in time and spatial resolution. We will perform our measurements not only on static structures, but on
complex structures under operating conditions. Finally as our equipment can also probe structural properties from microns to
single atom defects we can directly correlate our observations of electron dynamics with knowledge of geometrical structure. We
hope to directly answer central questions in nanophysics on how complex geometric structure on several length-scales induces
new and surprising electron dynamics and thus properties in nanoscale objects.
The low dimensional semiconductors and metal (nano) structures studied will be chosen to have unique novel properties that will
have potential applications in IT, life-science and renewable energy.
To radically increase our diagnostics capabilities we will combine PhotoEmission Electron Microscopy and attosecond XUV/IR
laser technology to directly image surface electron dynamics with attosecond time resolution and nanometer lateral resolution.
Exploring a completely new realm in terms of timescale with nm resolution we will start with rather simple structure such as Au
nanoparticles and arrays nanoholes in ultrathin metal films, and gradually increase complexity.
As the first group in the world we have shown that atomic resolved structural and electrical measurements by Scanning Tunneling
Microscopy is possible on complex 1D semiconductors heterostructures. Importantly, our new method allows for direct studies of
nanowires in devices.
We can now measure atomic scale surface chemistry and surface electronic/geometric structure directly on operational/operating
nanoscale devices. This is important both from a technology point of view, and is an excellent playground for understanding the
fundamental interplay between electronic and structural properties.
Max ERC Funding
1 419 120 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym ENDOSWITCH
Project Network Principles of Neuroendocrine Control:
Tuberoinfundibular Dopamine (TIDA) Oscillations and the Regulation of Lactation
Researcher (PI) Carl Christian Broberger
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The hypothalamus is essential for our survival and orchestrates every vital function of the body, from defence against predators and energy metabolism to reproduction. Yet, the network mechanisms underlying these actions remain largely hidden in a black box . Here, we will focus on the hypothalamic neuroendocrine system, where we have identified a novel robust network oscillation in the tuberoinfundibular dopamine (TIDA) neurons that control prolactin release. This oscillation is synchronized between neurons via gap junctions, and phasic firing is transformed into tonic discharge by compounds that functionally oppose neuroendocrine dopamine actions. Using this novel preparation, we will investigate the 1) the cellular (conductance) and network (connectivity) mechanisms underlying TIDA rhythmicity; 2) how TIDA activity is affected by hormones and transmitters that affect lactation; 3) the functional significance of phasic vs. tonic discharge in the regulation of dopamine release and lactation; and 4) the generality of TIDA cellular and network properties to other parvocellular neuron populations. These questions will be addressed through several in vitro and in vivo electrophysiological techniques, including slice whole-cell recording, extracellular in vivo recording, voltammetry and optical recording. These experiments will provide novel insight into the link between network interactions and behaviour, and have important clinical implications for e.g. endocrine and reproductive disorders.
Summary
The hypothalamus is essential for our survival and orchestrates every vital function of the body, from defence against predators and energy metabolism to reproduction. Yet, the network mechanisms underlying these actions remain largely hidden in a black box . Here, we will focus on the hypothalamic neuroendocrine system, where we have identified a novel robust network oscillation in the tuberoinfundibular dopamine (TIDA) neurons that control prolactin release. This oscillation is synchronized between neurons via gap junctions, and phasic firing is transformed into tonic discharge by compounds that functionally oppose neuroendocrine dopamine actions. Using this novel preparation, we will investigate the 1) the cellular (conductance) and network (connectivity) mechanisms underlying TIDA rhythmicity; 2) how TIDA activity is affected by hormones and transmitters that affect lactation; 3) the functional significance of phasic vs. tonic discharge in the regulation of dopamine release and lactation; and 4) the generality of TIDA cellular and network properties to other parvocellular neuron populations. These questions will be addressed through several in vitro and in vivo electrophysiological techniques, including slice whole-cell recording, extracellular in vivo recording, voltammetry and optical recording. These experiments will provide novel insight into the link between network interactions and behaviour, and have important clinical implications for e.g. endocrine and reproductive disorders.
Max ERC Funding
1 493 958 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym HALOGEN
Project Understanding Halogen Bonding in Solution: Investigation of Yet Unexplored Interactions with Applications in Medicinal Chemistry
Researcher (PI) Mate Erdelyi
Host Institution (HI) GOETEBORGS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), PE4, ERC-2010-StG_20091028
Summary Halogen bonding is an electron density donation-based weak interaction that has so far almost exclusively been investigated in computational and crystallographic studies. It shows high similarities to hydrogen bonding; however, its applicability for molecular recognition processes long remained unappreciated and has not been thoroughly explored.
The main goals of this project are (1) to take the major leap from solid state/computational to /solution/ investigations of halogen bonding by developing novel NMR methods, using these (2) perform the first ever systematic physicochemical study of halogen bonding in solutions, and (3) to apply the gained knowledge in structural biology through elucidation of the anaesthetic binding site of native proteins. This in turn is of direct clinical relevance by providing a long-sought understanding of the disease malignant hyperthermia.
Model compounds will be prepared using solution-phase and solid-supported organic synthesis; NMR methods will be developed for physicochemical studies of molecular recognition processes and applied in structural biology through the study of the interaction of anaesthetics with proteins involved in cellular calcium regulation.
Using a peptidomimetic model system and an outstandingly sensitive NMR technique I will systematically study the impact of halogen bond donor and acceptor sites, and of electronic and solvent effects on the strength of the interaction. The proposed method will quantify relative stability of a strategically-designed, cooperatively folding model system.
A second NMR technique will utilize paramagnetic effects and permit simultaneous characterization of bond strength and geometry of weak intermolecular complexes in solution. The technique will first be validated on small, organic model compounds and subsequently be transferred to weak, protein-ligand interactions. It will be exploited to gain an atomic level understanding of anaesthesia.
Summary
Halogen bonding is an electron density donation-based weak interaction that has so far almost exclusively been investigated in computational and crystallographic studies. It shows high similarities to hydrogen bonding; however, its applicability for molecular recognition processes long remained unappreciated and has not been thoroughly explored.
The main goals of this project are (1) to take the major leap from solid state/computational to /solution/ investigations of halogen bonding by developing novel NMR methods, using these (2) perform the first ever systematic physicochemical study of halogen bonding in solutions, and (3) to apply the gained knowledge in structural biology through elucidation of the anaesthetic binding site of native proteins. This in turn is of direct clinical relevance by providing a long-sought understanding of the disease malignant hyperthermia.
Model compounds will be prepared using solution-phase and solid-supported organic synthesis; NMR methods will be developed for physicochemical studies of molecular recognition processes and applied in structural biology through the study of the interaction of anaesthetics with proteins involved in cellular calcium regulation.
Using a peptidomimetic model system and an outstandingly sensitive NMR technique I will systematically study the impact of halogen bond donor and acceptor sites, and of electronic and solvent effects on the strength of the interaction. The proposed method will quantify relative stability of a strategically-designed, cooperatively folding model system.
A second NMR technique will utilize paramagnetic effects and permit simultaneous characterization of bond strength and geometry of weak intermolecular complexes in solution. The technique will first be validated on small, organic model compounds and subsequently be transferred to weak, protein-ligand interactions. It will be exploited to gain an atomic level understanding of anaesthesia.
Max ERC Funding
1 495 630 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
