Project acronym EURO-NEUROSTRESS
Project Dissecting the Central Stress Response: Bridging the Genotype-Phenotype Gap
Researcher (PI) Alon Chen
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression.
Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.
Summary
The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression.
Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym MIRNACLOCKNETWORKS
Project Towards a systemic view of the circadian clock: Integration of miRNAs into the molecular, cellular and neural circadian networks
Researcher (PI) Sebastian Kadener
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Circadian (24hs) rhythms in locomotor activity are one of the best-characterized behaviors at the molecular, cellular and neural levels. Despite that, our understanding of how these rhythms are generated is still limited. A major shortcoming of the current approaches in the field is that they depict the circadian clock as a mere addition of steps (and/or combination of parts). By doing so, the circadian oscillator is portrayed as a static rather than a dynamic system. We have recently shown for the first time that miRNA-mediated regulation plays a role in circadian timekeeping in Drosophila. In the present project we will exploit complementary and cutting-edge approaches that will provide an integrative and comprehensive view of the circadian timekeeping system. As we believe that miRNAs are key mediators of this integration, we will dissect their role in the circadian clock at the molecular, cellular and neural levels in Drosophila. At the molecular level, we will determine the mechanisms, and proteins that mediate the circadian regulation of miRNAs function. Moreover, by the use of high-throughput methodology we will assess and characterize the impact of translational regulation on both the circadian transcriptome and proteome. At the cellular level, we plan to determine how this type of regulation integrates with other circadian pathways and which specific pathways and proteins mediate this process. As a final goal of the proposed project we plan to generate a complete genetic interaction map of the known circadian regulators, which will integrate the different molecular and cellular events involved in timekeeping. This will be a key step towards the understanding of the circadian clock as a dynamic adjustable process. Last, but not least, we will study the role of miRNAs in the circadian neural network. For doing so we will set up an ex vivo approach (fly brain's culture) that will assess circadian parameters through fluorescent continuous live imaging.
Summary
Circadian (24hs) rhythms in locomotor activity are one of the best-characterized behaviors at the molecular, cellular and neural levels. Despite that, our understanding of how these rhythms are generated is still limited. A major shortcoming of the current approaches in the field is that they depict the circadian clock as a mere addition of steps (and/or combination of parts). By doing so, the circadian oscillator is portrayed as a static rather than a dynamic system. We have recently shown for the first time that miRNA-mediated regulation plays a role in circadian timekeeping in Drosophila. In the present project we will exploit complementary and cutting-edge approaches that will provide an integrative and comprehensive view of the circadian timekeeping system. As we believe that miRNAs are key mediators of this integration, we will dissect their role in the circadian clock at the molecular, cellular and neural levels in Drosophila. At the molecular level, we will determine the mechanisms, and proteins that mediate the circadian regulation of miRNAs function. Moreover, by the use of high-throughput methodology we will assess and characterize the impact of translational regulation on both the circadian transcriptome and proteome. At the cellular level, we plan to determine how this type of regulation integrates with other circadian pathways and which specific pathways and proteins mediate this process. As a final goal of the proposed project we plan to generate a complete genetic interaction map of the known circadian regulators, which will integrate the different molecular and cellular events involved in timekeeping. This will be a key step towards the understanding of the circadian clock as a dynamic adjustable process. Last, but not least, we will study the role of miRNAs in the circadian neural network. For doing so we will set up an ex vivo approach (fly brain's culture) that will assess circadian parameters through fluorescent continuous live imaging.
Max ERC Funding
1 478 606 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym RRHEDSPS
Project Reconsidering Representation: How Electoral Districts Shape Party Systems
Researcher (PI) Orit Kedar
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), SH2, ERC-2010-StG_20091209
Summary An electoral system is an essential component of representative democracy. It translates preferences
of citizens to a legislative body and inevitably distorts preferences, voicing some more loudly than others.
Theorizing and empirically analyzing how the electoral system tilts the playing ground is the aim of this
study.
The number of seats allotted to an electoral district—the district magnitude (DM)—is perhaps the
most important component defining an electoral system. It is long established that DM affects key features
of the political landscape in a country, such as representation, the number of parties, the type of government
(single- or multi-party coalition), parties’ strategy, voters’ consideration, and even redistribution policy.
Most democracies, however, have districts of many different magnitudes, and the range often reaches thirty
seats gap between the smallest and largest districts in a country. Districts in Portugal, for instance, vary
between two and forty-eight seats, and in Switzerland between one and thirty-five. The voluminous
literature on electoral districts uniformly sidesteps this heterogeneity, focusing instead on a single middle
district per country.
The proposed study is the first large-scale study that theorizes about and empirically analyzes the
effects of within-country district structure. I address questions such as: how does district heterogeneity
shape representation at the national level? How does it affect the party system? And how does it affect party
coordination?
In the first part of the study I will theorize about various aspects of district heterogeneity in a country
(e.g., skewness, effective number of magnitudes). I will gain deep understanding for district distributions
and develop politically-relevant measures of heterogeneity. Drawing on insights from the theoretical part,
the second part will empirically examine how district heterogeneity affects the political landscape, and in
particular representation, party system, and party coordination. This part relies on extensive district- and
national-level data collection and data analysis in OECD countries as well as in-depth case analysis.
Analyzing the effect of district heterogeneity on representation, party systems, and party
coordination will open new avenues of research about design of electoral systems.
Summary
An electoral system is an essential component of representative democracy. It translates preferences
of citizens to a legislative body and inevitably distorts preferences, voicing some more loudly than others.
Theorizing and empirically analyzing how the electoral system tilts the playing ground is the aim of this
study.
The number of seats allotted to an electoral district—the district magnitude (DM)—is perhaps the
most important component defining an electoral system. It is long established that DM affects key features
of the political landscape in a country, such as representation, the number of parties, the type of government
(single- or multi-party coalition), parties’ strategy, voters’ consideration, and even redistribution policy.
Most democracies, however, have districts of many different magnitudes, and the range often reaches thirty
seats gap between the smallest and largest districts in a country. Districts in Portugal, for instance, vary
between two and forty-eight seats, and in Switzerland between one and thirty-five. The voluminous
literature on electoral districts uniformly sidesteps this heterogeneity, focusing instead on a single middle
district per country.
The proposed study is the first large-scale study that theorizes about and empirically analyzes the
effects of within-country district structure. I address questions such as: how does district heterogeneity
shape representation at the national level? How does it affect the party system? And how does it affect party
coordination?
In the first part of the study I will theorize about various aspects of district heterogeneity in a country
(e.g., skewness, effective number of magnitudes). I will gain deep understanding for district distributions
and develop politically-relevant measures of heterogeneity. Drawing on insights from the theoretical part,
the second part will empirically examine how district heterogeneity affects the political landscape, and in
particular representation, party system, and party coordination. This part relies on extensive district- and
national-level data collection and data analysis in OECD countries as well as in-depth case analysis.
Analyzing the effect of district heterogeneity on representation, party systems, and party
coordination will open new avenues of research about design of electoral systems.
Max ERC Funding
1 038 686 €
Duration
Start date: 2010-11-01, End date: 2016-10-31
Project acronym SIAMCP
Project Follow the PAIN: Novel Somatotopically-Based Integrative Approach to Study Mechanisms of Detection, Transmission and Perpetuation of Nociceptive, Inflammatory and Neuropathic Pain
Researcher (PI) Alexander Binshtok
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The worst of evils - pain is one of the main reasons for seeking medical help. Chronic pain affects almost one fifth of the population of Europe and leads to exorbitant medical expenses as well as extreme suffering. Despite extensive efforts, effective pain treatment has remained elusive. Inadequate understanding of the mechanisms of pain prevents the development of effective therapies. In order to better understand pain mechanisms, a novel integrative approach is needed. This approach should: to investigate the fundamental site of signal detection; the nociceptive terminals and to establish an understanding of the progression from peripheral nociception to central pain perception. Our project aims to integrate analysis at different levels of pain perception in normal and pathological conditions in order to elucidate mechanisms underlying chronic pain. Our approach propose to study pain related mechanisms along somatotopically define neuroaxis of vibrissae-barrel system. Using this unique system where peripheral receptor directly corresponds to its central analyzer, we will first characterize noxious signal detection by single channels in individual nociceptive terminal. We will follow propagation of nociceptive signal and monitor activity-dependent changes in corresponding circuits at trigeminal nuclei, thalamus and cortex. We will study modulation in of synaptic connectivity in the spino-thalamo-cortical pathway in models of chronic pain. This multi-disciplinary project will incorporate ground-breaking imaging techniques and state-of-the-art electrophysiological, histological and behavioural experiments to study pain-related mechanisms at the molecular and cellular levels as well as at the level of neuronal networks and behaviour.
Summary
The worst of evils - pain is one of the main reasons for seeking medical help. Chronic pain affects almost one fifth of the population of Europe and leads to exorbitant medical expenses as well as extreme suffering. Despite extensive efforts, effective pain treatment has remained elusive. Inadequate understanding of the mechanisms of pain prevents the development of effective therapies. In order to better understand pain mechanisms, a novel integrative approach is needed. This approach should: to investigate the fundamental site of signal detection; the nociceptive terminals and to establish an understanding of the progression from peripheral nociception to central pain perception. Our project aims to integrate analysis at different levels of pain perception in normal and pathological conditions in order to elucidate mechanisms underlying chronic pain. Our approach propose to study pain related mechanisms along somatotopically define neuroaxis of vibrissae-barrel system. Using this unique system where peripheral receptor directly corresponds to its central analyzer, we will first characterize noxious signal detection by single channels in individual nociceptive terminal. We will follow propagation of nociceptive signal and monitor activity-dependent changes in corresponding circuits at trigeminal nuclei, thalamus and cortex. We will study modulation in of synaptic connectivity in the spino-thalamo-cortical pathway in models of chronic pain. This multi-disciplinary project will incorporate ground-breaking imaging techniques and state-of-the-art electrophysiological, histological and behavioural experiments to study pain-related mechanisms at the molecular and cellular levels as well as at the level of neuronal networks and behaviour.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
