Project acronym 5HT-OPTOGENETICS
Project Optogenetic Analysis of Serotonin Function in the Mammalian Brain
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Summary
Serotonin (5-HT) is implicated in a wide spectrum of brain functions and disorders. However, its functions remain controversial and enigmatic. We suggest that past work on the 5-HT system have been significantly hampered by technical limitations in the selectivity and temporal resolution of the conventional pharmacological and electrophysiological methods that have been applied. We therefore propose to apply novel optogenetic methods that will allow us to overcome these limitations and thereby gain new insight into the biological functions of this important molecule. In preliminary studies, we have demonstrated that we can deliver exogenous proteins specifically to 5-HT neurons using viral vectors. Our objectives are to (1) record, (2) stimulate and (3) silence the activity of 5-HT neurons with high molecular selectivity and temporal precision by using genetically-encoded sensors, activators and inhibitors of neural function. These tools will allow us to monitor and control the 5-HT system in real-time in freely-behaving animals and thereby to establish causal links between information processing in 5-HT neurons and specific behaviors. In combination with quantitative behavioral assays, we will use this approach to define the role of 5-HT in sensory, motor and cognitive functions. The significance of the work is three-fold. First, we will establish a new arsenal of tools for probing the physiological and behavioral functions of 5-HT neurons. Second, we will make definitive tests of major hypotheses of 5-HT function. Third, we will have possible therapeutic applications. In this way, the proposed work has the potential for a major impact in research on the role of 5-HT in brain function and dysfunction.
Max ERC Funding
2 318 636 €
Duration
Start date: 2010-07-01, End date: 2015-12-31
Project acronym IPLASTICITY
Project Induction of juvenile-like plasticity in the adult brain
Researcher (PI) Eero Castrén
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. In a series of landmark studies, we have shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. These ground-breaking studies establish a new principle, induced juvenile-like plasticity (iPlasticity) and define a new class of drugs, iPlastic drugs. For optimal results, iPlastic drug must be combined with physical or psychological rehabilitation, which guide the plastic networks and together allow better adaptation towards changing environment. iPlasticity may facilitate functional recovery after brain injury and underlie the enhanced efficacy of combined antidepressant treatment and psychotherapy.
We have uncovered iPlasticity as an exciting new concept and established experimental models to study the molecular, cellular and network level mechanisms underlying it. We will here focus on the role of neurotrophin BDNF, because our previous and unpublished work clearly shows that BDNF and its receptors TrkB and p75 are essential and sufficient for iPlasticity. We have found that a major developmental reorganization in TrkB signalling takes place coinciding with the end of critical periods, and its reversal may underlie iPlasticity. We will utilize our resources as a leading lab in BDNF effects in adult brain and through novel controlled transgenic models, genomics and proteomics, we will reveal the role of BDNF signalling through TrkB and p75 in brain maturation, iPlasticity and brain disorders. Understanding the neurobiological background of iPlasticity will be vital for iPlastic drug development and the numerous translational applications of iPlasticity clearly in sight.
Summary
Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. In a series of landmark studies, we have shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. These ground-breaking studies establish a new principle, induced juvenile-like plasticity (iPlasticity) and define a new class of drugs, iPlastic drugs. For optimal results, iPlastic drug must be combined with physical or psychological rehabilitation, which guide the plastic networks and together allow better adaptation towards changing environment. iPlasticity may facilitate functional recovery after brain injury and underlie the enhanced efficacy of combined antidepressant treatment and psychotherapy.
We have uncovered iPlasticity as an exciting new concept and established experimental models to study the molecular, cellular and network level mechanisms underlying it. We will here focus on the role of neurotrophin BDNF, because our previous and unpublished work clearly shows that BDNF and its receptors TrkB and p75 are essential and sufficient for iPlasticity. We have found that a major developmental reorganization in TrkB signalling takes place coinciding with the end of critical periods, and its reversal may underlie iPlasticity. We will utilize our resources as a leading lab in BDNF effects in adult brain and through novel controlled transgenic models, genomics and proteomics, we will reveal the role of BDNF signalling through TrkB and p75 in brain maturation, iPlasticity and brain disorders. Understanding the neurobiological background of iPlasticity will be vital for iPlastic drug development and the numerous translational applications of iPlasticity clearly in sight.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym NEUROHABIT
Project Neural mechanisms of action learning and action selection: from intent to habit
Researcher (PI) Rui Manuel Marques Fernandes Da Costa
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary In every day life, we constantly have to select the appropriate actions to obtain specific outcomes. Actions can be selected based on their consequences, for example when we press an elevator button to get to the particular floor where we live. This goal-directed behaviour is crucial to face the ever-changing environment but demands an effortful control and monitoring of the response; one way to balance the need for flexibility and efficiency is through automatization of recurring decision processes as a habit. Habitual responses no longer need the evaluation of their consequences, and can be elicited by particular situations or stimuli, for example when we press the button for our home floor in a building that we are visiting for the first time. There is growing evidence that the neural circuits underlying intentional or goal-directed actions are different from those underlying habits; associative corticostriatal circuits have been implicated in goal-directed actions, and sensorimotor circuits in habit formation. Dopamine (DA) has been implicated in both voluntary actions and habits. However, DA neurons from the VTA and the SNc project to different cortical and striatal regions, and the specific role of VTA and SNc DA in goal-directed actions and habits has not been clarified. We propose to: 1) use cell-type and region specific genetic manipulations to test if phasic firing in VTA or SNc DA neurons is necessary for goal-directed actions or habits, respectively, 2) generate cell-type specific channelrodhopsin transgenic mice to test if phasic DA neuron firing in these areas is sufficient to produce goal-directed actions or habits, and 3) selectively manipulate striatal neurons modulated by VTA or SNc phasic DA to test if they are necessary for goal-directed actions or habits. The dissection of the molecular and circuit mechanisms underlying goal-directed and habitual responses will be critical to understand decision-making, and the origins of compulsive behaviour.
Summary
In every day life, we constantly have to select the appropriate actions to obtain specific outcomes. Actions can be selected based on their consequences, for example when we press an elevator button to get to the particular floor where we live. This goal-directed behaviour is crucial to face the ever-changing environment but demands an effortful control and monitoring of the response; one way to balance the need for flexibility and efficiency is through automatization of recurring decision processes as a habit. Habitual responses no longer need the evaluation of their consequences, and can be elicited by particular situations or stimuli, for example when we press the button for our home floor in a building that we are visiting for the first time. There is growing evidence that the neural circuits underlying intentional or goal-directed actions are different from those underlying habits; associative corticostriatal circuits have been implicated in goal-directed actions, and sensorimotor circuits in habit formation. Dopamine (DA) has been implicated in both voluntary actions and habits. However, DA neurons from the VTA and the SNc project to different cortical and striatal regions, and the specific role of VTA and SNc DA in goal-directed actions and habits has not been clarified. We propose to: 1) use cell-type and region specific genetic manipulations to test if phasic firing in VTA or SNc DA neurons is necessary for goal-directed actions or habits, respectively, 2) generate cell-type specific channelrodhopsin transgenic mice to test if phasic DA neuron firing in these areas is sufficient to produce goal-directed actions or habits, and 3) selectively manipulate striatal neurons modulated by VTA or SNc phasic DA to test if they are necessary for goal-directed actions or habits. The dissection of the molecular and circuit mechanisms underlying goal-directed and habitual responses will be critical to understand decision-making, and the origins of compulsive behaviour.
Max ERC Funding
1 526 304 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym NUCLEARACTIN
Project Actin as the Master Organizer of Nuclear Structure and Function
Researcher (PI) Maria Kristina Vartiainen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary Unlike previously thought the nucleus is a highly compartmentalized organelle. Both the genome and processes associated with it show non-random distribution within the nucleus. This compartmentalization has a fundamental impact on nuclear processes. However, the mechanisms driving this organization are poorly understood. I hypothesize that actin plays a key role in this process. Nevertheless, the true potential of nuclear actin has not been fully appreciated, due to two fundamental open questions in this field, namely 1) what is the biological significance of nuclear actin and 2) what is the molecular mechanism by which actin operates in the nucleus? I intend to address these key questions by manipulating actin specifically in the nucleus, and by identifying nuclear actin binding partners, respectively. My lab has recently identified the nuclear import mechanism for actin, which offers us a unique tool to manipulate nuclear actin. We will therefore create cell lines with decreased/increased nuclear actin, and analyze the consequences by using cell biological and gene expression tools, combined with deep sequencing. This will disclose the genes that depend on actin for their expression, and reveal the biological significance of nuclear actin in organizing the general nuclear landscape. To unravel the mechanisms by which actin functions in the nucleus, we will implement a novel multi-readout, fluorescence microscopy screen to identify nuclear actin binding proteins, which will be analyzed by different biochemical methods. This approach will reveal how actin is connected to nuclear machineries, and what biochemical features of actin are required to power the essential nuclear processes. These techniques will significantly broaden our understanding on the nuclear functions of actin, and thus likely reveal molecular mechanisms that regulate nuclear organization, which are highly relevant to basic biological processes, such as cell differentiation and epigenetics.
Summary
Unlike previously thought the nucleus is a highly compartmentalized organelle. Both the genome and processes associated with it show non-random distribution within the nucleus. This compartmentalization has a fundamental impact on nuclear processes. However, the mechanisms driving this organization are poorly understood. I hypothesize that actin plays a key role in this process. Nevertheless, the true potential of nuclear actin has not been fully appreciated, due to two fundamental open questions in this field, namely 1) what is the biological significance of nuclear actin and 2) what is the molecular mechanism by which actin operates in the nucleus? I intend to address these key questions by manipulating actin specifically in the nucleus, and by identifying nuclear actin binding partners, respectively. My lab has recently identified the nuclear import mechanism for actin, which offers us a unique tool to manipulate nuclear actin. We will therefore create cell lines with decreased/increased nuclear actin, and analyze the consequences by using cell biological and gene expression tools, combined with deep sequencing. This will disclose the genes that depend on actin for their expression, and reveal the biological significance of nuclear actin in organizing the general nuclear landscape. To unravel the mechanisms by which actin functions in the nucleus, we will implement a novel multi-readout, fluorescence microscopy screen to identify nuclear actin binding proteins, which will be analyzed by different biochemical methods. This approach will reveal how actin is connected to nuclear machineries, and what biochemical features of actin are required to power the essential nuclear processes. These techniques will significantly broaden our understanding on the nuclear functions of actin, and thus likely reveal molecular mechanisms that regulate nuclear organization, which are highly relevant to basic biological processes, such as cell differentiation and epigenetics.
Max ERC Funding
1 491 484 €
Duration
Start date: 2012-11-01, End date: 2018-08-31
Project acronym PAPS&PUPS
Project Regulation of Gene Expression by non-canonical poly(A) and poly(U) polymerases
Researcher (PI) Andrzej Dziembowski
Host Institution (HI) INSTYTUT BIOCHEMII I BIOFIZYKI POLSKIEJ AKADEMII NAUK
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Summary
In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym TLIM
Project Talent and Learning in Imperfect Markets
Researcher (PI) Marko Juhani Terviö
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), SH1, ERC-2009-StG
Summary The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
Summary
The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
Max ERC Funding
1 003 440 €
Duration
Start date: 2009-10-01, End date: 2015-03-31
Project acronym Universal Banking
Project Universal Banking, Corporate Control and Crises
Researcher (PI) Miguel Luis Sousa De Almeida Ferreira
Host Institution (HI) FACULDADE DE ECONOMIA DA UNIVERSIDADE NOVA DE LISBOA
Call Details Starting Grant (StG), SH1, ERC-2012-StG_20111124
Summary Financial intermediaries play a vital role in providing capital to corporations. The 2007-2009 financial crisis had dramatic consequences on the organization of the financial system that led to the rise of universal banking and financial conglomerates. Financial conglomerates have been common in Europe, but the recent developments have eroded the separation of commercial and investment banking elsewhere. Financial conglomerates act as lenders but also underwrite and trade securities, have equity stakes and sit on the board of corporations, and manage mutual and pension funds that invest in corporations. These forms of corporate control by financial conglomerates are distinct in their incentives and costs and therefore can have distinct effects on non-financial corporations. We will study the effect of control by financial conglomerates on corporation’s performance, investment, financing, and corporate governance policies. A particular relevant channel through which financial conglomerates can affect firm’s policies is the credit channel. Firms establish relationships with financial conglomerates that give easier access to credit and potentially at a lower cost due to economies of scale in information collection and monitoring. There may be, however, costs to firms with a close relationship with a financial conglomerate as firms may be locked up due to an information monopoly. We will study the effects of bank-firm relationships on the loan market. In particular, we will examine the importance of these relationships for explaining differences in the cost of bank distress across firms. The hypothesis is that strong ties with banks reduce firms’ ability to substitute relationship bank loans with other sources of external finance, and therefore firms with stronger relationships could experience greater costs during financial crises. We will contribute to the understanding the consequences of shocks to the financial health of banks for nonfinancial firms.
Summary
Financial intermediaries play a vital role in providing capital to corporations. The 2007-2009 financial crisis had dramatic consequences on the organization of the financial system that led to the rise of universal banking and financial conglomerates. Financial conglomerates have been common in Europe, but the recent developments have eroded the separation of commercial and investment banking elsewhere. Financial conglomerates act as lenders but also underwrite and trade securities, have equity stakes and sit on the board of corporations, and manage mutual and pension funds that invest in corporations. These forms of corporate control by financial conglomerates are distinct in their incentives and costs and therefore can have distinct effects on non-financial corporations. We will study the effect of control by financial conglomerates on corporation’s performance, investment, financing, and corporate governance policies. A particular relevant channel through which financial conglomerates can affect firm’s policies is the credit channel. Firms establish relationships with financial conglomerates that give easier access to credit and potentially at a lower cost due to economies of scale in information collection and monitoring. There may be, however, costs to firms with a close relationship with a financial conglomerate as firms may be locked up due to an information monopoly. We will study the effects of bank-firm relationships on the loan market. In particular, we will examine the importance of these relationships for explaining differences in the cost of bank distress across firms. The hypothesis is that strong ties with banks reduce firms’ ability to substitute relationship bank loans with other sources of external finance, and therefore firms with stronger relationships could experience greater costs during financial crises. We will contribute to the understanding the consequences of shocks to the financial health of banks for nonfinancial firms.
Max ERC Funding
1 174 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
