Project acronym LearnAnx_CircAmyg
Project Learning and Anxiety in Amygdala-based Neural Circuits
Researcher (PI) Rony PAZ
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Major advances were made in understanding circuits that underlie aversive emotional learning. The majority gained by using classical associative models, mainly tone/context-shock conditioning. Failure to extinguish the response or to discriminate from other safe stimuli (generalization), form two main animal models for human anxiety-disorders and post-traumatic-stress. These simple yet powerful approaches enabled cutting-edge techniques in rodents to unveil amygdala circuitry and its connectivity with the medial-prefrontal-cortex. Yet, we have less understanding of the mechanisms that underlie elaborated behavioural models of mal-adaptive behaviour, as well as less understanding of neural codes and computations in the evolutionary-expanded primate amygdala. Our lab recently embarked on exploring these venues by pioneering physiological studies of generalization and extinction protocols in primates. The goal of the current project is to develop behavioural models of complex learning and maladaptive behaviour, and then examine and shed light on the underlying computations in primate amygdala-PFC circuit. We design a novel rule-based learning task, and examine its acquisition, extinction, generalization and exploration-exploitation trade-off in dangerous environments. Specifically, the concepts of rule learning and exploration-exploitation tradeoff form novel insights and aspects of [mal-]adaptive behaviours, and will suggest new animal models of learned anxiety. We record dozens of neurons in the amygdala and prefrontal-cortex simultaneously using deep multi-contact arrays, supplemented by stimulation to address functional connectivity, and development of modelling approaches for the behaviour and neural codes. We posit that the development of more [complex] models is crucial and the next logical step in achieving translation of animal models of anxiety disorders, as well as in understanding basic mechanisms behind the rich repertoire of emotional behaviours.
Summary
Major advances were made in understanding circuits that underlie aversive emotional learning. The majority gained by using classical associative models, mainly tone/context-shock conditioning. Failure to extinguish the response or to discriminate from other safe stimuli (generalization), form two main animal models for human anxiety-disorders and post-traumatic-stress. These simple yet powerful approaches enabled cutting-edge techniques in rodents to unveil amygdala circuitry and its connectivity with the medial-prefrontal-cortex. Yet, we have less understanding of the mechanisms that underlie elaborated behavioural models of mal-adaptive behaviour, as well as less understanding of neural codes and computations in the evolutionary-expanded primate amygdala. Our lab recently embarked on exploring these venues by pioneering physiological studies of generalization and extinction protocols in primates. The goal of the current project is to develop behavioural models of complex learning and maladaptive behaviour, and then examine and shed light on the underlying computations in primate amygdala-PFC circuit. We design a novel rule-based learning task, and examine its acquisition, extinction, generalization and exploration-exploitation trade-off in dangerous environments. Specifically, the concepts of rule learning and exploration-exploitation tradeoff form novel insights and aspects of [mal-]adaptive behaviours, and will suggest new animal models of learned anxiety. We record dozens of neurons in the amygdala and prefrontal-cortex simultaneously using deep multi-contact arrays, supplemented by stimulation to address functional connectivity, and development of modelling approaches for the behaviour and neural codes. We posit that the development of more [complex] models is crucial and the next logical step in achieving translation of animal models of anxiety disorders, as well as in understanding basic mechanisms behind the rich repertoire of emotional behaviours.
Max ERC Funding
1 981 175 €
Duration
Start date: 2017-09-01, End date: 2022-07-31
Project acronym MacroStability
Project Stability and dynamics at different spatial scales: From physiology to Alzheimer's degeneration
Researcher (PI) Inna Slutsky
Host Institution (HI) TEL AVIV UNIVERSITY
Country Israel
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains one of the most fundamental questions in neuroscience. Empirical and theoretical studies suggest that homeostatic negative feedback mechanisms operate to stabilize the function of a system at a set point level of activity. While extensive research uncovered diverse homeostatic mechanisms that maintain activity of neural circuits at extended timescales, several key questions remain open. First, what are the basic principles and the molecular machinery underlying invariant population dynamics of neural circuits, composed from intrinsically unstable activity patterns of individual neurons? Second, is homeostatic regulation compromised in Alzheimer's disease (AD) and do homeostatic failures lead to aberrant brain activity and memory decline, the overlapping phenotypes of AD and many other distinct neurodegenerative disorders? And finally, how do homeostatic systems operate in vivo under experience-dependent changes in firing rates and patterns?
To target these questions, we have developed an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations, signaling processes at the level of single synapses and neuronal meta-plasticity. We will focus on hippocampal circuitry and combine ex vivo electrophysiology, single- and two-photon excitation imaging, time-resolved fluorescence microscopy and molecular biology, together with longitudinal monitoring of activity from large populations of hippocampal neurons in freely behaving mice. Utilizing these state-of-the-art approaches, we will determine how firing stability is maintained at different spatial scales and what are the mechanisms leading to destabilization of firing patterns in AD-related context. The proposed research will elucidate fundamental principles of neuronal function and offer conceptual insights into AD pathophysiology.
Summary
How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains one of the most fundamental questions in neuroscience. Empirical and theoretical studies suggest that homeostatic negative feedback mechanisms operate to stabilize the function of a system at a set point level of activity. While extensive research uncovered diverse homeostatic mechanisms that maintain activity of neural circuits at extended timescales, several key questions remain open. First, what are the basic principles and the molecular machinery underlying invariant population dynamics of neural circuits, composed from intrinsically unstable activity patterns of individual neurons? Second, is homeostatic regulation compromised in Alzheimer's disease (AD) and do homeostatic failures lead to aberrant brain activity and memory decline, the overlapping phenotypes of AD and many other distinct neurodegenerative disorders? And finally, how do homeostatic systems operate in vivo under experience-dependent changes in firing rates and patterns?
To target these questions, we have developed an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations, signaling processes at the level of single synapses and neuronal meta-plasticity. We will focus on hippocampal circuitry and combine ex vivo electrophysiology, single- and two-photon excitation imaging, time-resolved fluorescence microscopy and molecular biology, together with longitudinal monitoring of activity from large populations of hippocampal neurons in freely behaving mice. Utilizing these state-of-the-art approaches, we will determine how firing stability is maintained at different spatial scales and what are the mechanisms leading to destabilization of firing patterns in AD-related context. The proposed research will elucidate fundamental principles of neuronal function and offer conceptual insights into AD pathophysiology.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym Mideast Med
Project A regional history of medicine in the modern Middle East, 1830-1960
Researcher (PI) Liat KOZMA
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Consolidator Grant (CoG), SH6, ERC-2016-COG
Summary The purpose of this project is to write a long-term regional history of medicine in the Middle East and North Africa from a transnational and multi-layered perspective. A regional approach will enable tracing both global influences and local specificities, while a long-term perspective (1830-1960) will allow tracing continuity and change from the late Ottoman Middle East through the colonial to the post-colonial periods. Combining archival and published sources in Arabic, French, English, Hebrew, English, German and Ottoman Turkish, it will offer a unique perspective into the formation of the modern Middle East.
Research for this project will revolve around five main cores: First, the global context: global vectors of disease transmission, alongside the transmission of medical knowledge and expertise. Second, the international aspect: how international conventions and international bodies affected the region and were affected by it. Third, the regional flow of both health challenges and proposed solutions, the regional spread of epidemics and the formation of regional epistemic communities. Fourth, the colonial aspect, noting both inter- and intra-colonial influences, and the encounter between colonial bodies of knowledge and locally produced ones. Fifth, the role played by doctors in various national projects: the nahda, namely the Arabic literary revival from the mid-nineteenth century onwards; the Zionist project; Egyptian and Syrian interwar nationalism and, later, Arab nationalism.
This project will portray an intersection between the corporal, the social, the cultural and the technological and trace these interconnections across time and space. Health, medicine and hygiene will be a prism through which to explore large processes, such as colonization and decolonization, national identity and state-building. The scientific development of medicine and the globalization of health-risks and medical knowledge in this period make medicine an ideal case study.
Summary
The purpose of this project is to write a long-term regional history of medicine in the Middle East and North Africa from a transnational and multi-layered perspective. A regional approach will enable tracing both global influences and local specificities, while a long-term perspective (1830-1960) will allow tracing continuity and change from the late Ottoman Middle East through the colonial to the post-colonial periods. Combining archival and published sources in Arabic, French, English, Hebrew, English, German and Ottoman Turkish, it will offer a unique perspective into the formation of the modern Middle East.
Research for this project will revolve around five main cores: First, the global context: global vectors of disease transmission, alongside the transmission of medical knowledge and expertise. Second, the international aspect: how international conventions and international bodies affected the region and were affected by it. Third, the regional flow of both health challenges and proposed solutions, the regional spread of epidemics and the formation of regional epistemic communities. Fourth, the colonial aspect, noting both inter- and intra-colonial influences, and the encounter between colonial bodies of knowledge and locally produced ones. Fifth, the role played by doctors in various national projects: the nahda, namely the Arabic literary revival from the mid-nineteenth century onwards; the Zionist project; Egyptian and Syrian interwar nationalism and, later, Arab nationalism.
This project will portray an intersection between the corporal, the social, the cultural and the technological and trace these interconnections across time and space. Health, medicine and hygiene will be a prism through which to explore large processes, such as colonization and decolonization, national identity and state-building. The scientific development of medicine and the globalization of health-risks and medical knowledge in this period make medicine an ideal case study.
Max ERC Funding
1 867 181 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym ONCOmetENHANCERS
Project Elucidating the Role of Enhancer Methylation Variation in Cancer and Developing Enhancer-based Markers and Targets for Precision Medicine
Researcher (PI) Asaf Hellman
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Consolidator Grant (CoG), LS4, ERC-2016-COG
Summary Cancer is a growing medical problem which genetic and environmental basis is not clearly understood. Massive efforts over the last decade have identified differences in cancer gene expression that cannot be explained by coding sequences or promoter variations, whereas the effect of transcriptional enhancers remains unclear due to the lack of an effective way to link enhancers with their controlled genes. Recently, we discovered a class of inter-tumor, inter-patient DNA methylation variations in putative enhancers that predict changes in gene expression levels with much greater power than promoter or sequence analyses. The overall goal of this proposal is to determine if changes in enhancer methylation form part of the genomic basis of cancer. Our aim is to elucidate methylation-influenced disease regulatory circuits that affect cancer driver and risk genes and may ultimately serve as markers for disease progression and drug response. Utilizing a new genomic methodology, which allows systematic prediction and verification of gene-enhancer pairing, I will test the above hypothesis in two disease models: breast cancer and glioblastoma. I will methodologically assess numerous potential enhancers across the disease genomes and explore the effects of genetic and epigenetic mutations and variations at these sites. Informative sites will then be evaluated as markers of gene expression level in tumor biopsies. Ultimately, I will apply novel tools to manipulate selected enhancers genetically and epigenetically, thus investigating the causal relationships between enhancer methylation and gene expression, and assessing the potential for tuning gene expression levels by enhancer methylation modification. This study may transform our understanding of the mechanisms underlying disease predisposition, determine the regulatory circuits of key disease genes, lead to improved diagnosis and predictive abilities, and may pave the way for precision epigenetic therapy.
Summary
Cancer is a growing medical problem which genetic and environmental basis is not clearly understood. Massive efforts over the last decade have identified differences in cancer gene expression that cannot be explained by coding sequences or promoter variations, whereas the effect of transcriptional enhancers remains unclear due to the lack of an effective way to link enhancers with their controlled genes. Recently, we discovered a class of inter-tumor, inter-patient DNA methylation variations in putative enhancers that predict changes in gene expression levels with much greater power than promoter or sequence analyses. The overall goal of this proposal is to determine if changes in enhancer methylation form part of the genomic basis of cancer. Our aim is to elucidate methylation-influenced disease regulatory circuits that affect cancer driver and risk genes and may ultimately serve as markers for disease progression and drug response. Utilizing a new genomic methodology, which allows systematic prediction and verification of gene-enhancer pairing, I will test the above hypothesis in two disease models: breast cancer and glioblastoma. I will methodologically assess numerous potential enhancers across the disease genomes and explore the effects of genetic and epigenetic mutations and variations at these sites. Informative sites will then be evaluated as markers of gene expression level in tumor biopsies. Ultimately, I will apply novel tools to manipulate selected enhancers genetically and epigenetically, thus investigating the causal relationships between enhancer methylation and gene expression, and assessing the potential for tuning gene expression levels by enhancer methylation modification. This study may transform our understanding of the mechanisms underlying disease predisposition, determine the regulatory circuits of key disease genes, lead to improved diagnosis and predictive abilities, and may pave the way for precision epigenetic therapy.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym Struct. vs. Individ
Project The ‘Declining Significance of Gender’ Reexamined: Cross-Country Comparison of Individual and Structural Aspects of Gender Inequality
Researcher (PI) Hadas Mandel Levy
Host Institution (HI) TEL AVIV UNIVERSITY
Country Israel
Call Details Consolidator Grant (CoG), SH3, ERC-2016-COG
Summary The comparative research of long-term trends largely neglects structural mechanisms of gender inequality, i.e. the gender bias in which jobs and activities are evaluated and rewarded. I argue that as more women become integrated in positions of power, the stronger the role of structural elements is likely to become. However, because these are less visible and amenable to empirical assessment, they are under-researched compared to individual aspects, and are commonly assumed to be gender-neutral. The implication is that the importance of gender as a determinant of economic inequality in the labour market becomes insufficiently acknowledged, and thus difficult to track and eradicate.
My empirical objective is to track structural vs. individual processes of gender inequality over a period of 40 years, using the case of occupations. My aim is to uncover the countervailing processes of women’s (individual) upward occupational mobility versus women’s (collective) effect on occupational pay. I argue that the effects of structural aspects of gender inequality increase over time, but are concealed by women’s (individual) upward mobility.
I expect the dynamic of the two processes to vary between countries and also by class. I thus seek to examine the processes in four representative countries – Sweden, Germany, Spain and the United States – that differ in many of the institutional aspects that affect gender inequality, including the provision of welfare, gender ideology, wage structure, and political economy factors. Therefore, gender in/equality processes in these countries are expected to take different forms in both structural and individual appearances. That said, in all countries I expect gender equality processes to be more pronounced and rapid for advantaged women. At the structural level, however, the rapid upward occupational mobility of skilled and educated women may expose highly rewarded occupations to devaluation and pay reduction more than others.
Summary
The comparative research of long-term trends largely neglects structural mechanisms of gender inequality, i.e. the gender bias in which jobs and activities are evaluated and rewarded. I argue that as more women become integrated in positions of power, the stronger the role of structural elements is likely to become. However, because these are less visible and amenable to empirical assessment, they are under-researched compared to individual aspects, and are commonly assumed to be gender-neutral. The implication is that the importance of gender as a determinant of economic inequality in the labour market becomes insufficiently acknowledged, and thus difficult to track and eradicate.
My empirical objective is to track structural vs. individual processes of gender inequality over a period of 40 years, using the case of occupations. My aim is to uncover the countervailing processes of women’s (individual) upward occupational mobility versus women’s (collective) effect on occupational pay. I argue that the effects of structural aspects of gender inequality increase over time, but are concealed by women’s (individual) upward mobility.
I expect the dynamic of the two processes to vary between countries and also by class. I thus seek to examine the processes in four representative countries – Sweden, Germany, Spain and the United States – that differ in many of the institutional aspects that affect gender inequality, including the provision of welfare, gender ideology, wage structure, and political economy factors. Therefore, gender in/equality processes in these countries are expected to take different forms in both structural and individual appearances. That said, in all countries I expect gender equality processes to be more pronounced and rapid for advantaged women. At the structural level, however, the rapid upward occupational mobility of skilled and educated women may expose highly rewarded occupations to devaluation and pay reduction more than others.
Max ERC Funding
1 395 000 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
