Project acronym BRAINCODES
Project Brain networks controlling social decisions
Researcher (PI) Christian Carl RUFF
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Consolidator Grant (CoG), SH4, ERC-2016-COG
Summary Successful social interactions require social decision making, the ability to guide our actions in line with the goals and expectations of the people around us. Disordered social decision making – e.g., associated with criminal activity or psychiatric illnesses – poses significant financial and personal challenges to society. However, the brain mechanisms that enable us to control our social behavior are far from being understood. Here I will take decisive steps towards a causal understanding of these mechanisms by elucidating the role of functional interactions in the brain networks responsible for steering strategic, prosocial, and norm-compliant behavior. I will employ a unique multi-method approach that integrates computational modeling of social decisions with new combinations of multimodal neuroimaging and brain stimulation methods. Using EEG-fMRI, I will first identify spatio-temporal patterns of functional interactions between brain areas that correlate with social decision processes as identified by computational modeling of behavior in different economic games. In combined brain stimulation-fMRI studies, I will then attempt to affect – and in fact enhance – these social decision-making processes by modulating the identified brain network patterns with novel, targeted brain stimulation protocols and measuring the resulting effects on behavior and brain activity. Finally, I will examine whether the identified brain network mechanisms are indeed related to disturbed social decisions in two psychiatric illnesses characterized by maladaptive social behavior (post-traumatic stress disorder and autism spectrum disorder). My proposed work plan will generate a causal understanding of the brain network mechanisms that allow humans to control their social decisions, thereby elucidating a biological basis for individual differences in social behavior and paving the way for new perspectives on how disordered social behavior may be identified and hopefully remedied.
Summary
Successful social interactions require social decision making, the ability to guide our actions in line with the goals and expectations of the people around us. Disordered social decision making – e.g., associated with criminal activity or psychiatric illnesses – poses significant financial and personal challenges to society. However, the brain mechanisms that enable us to control our social behavior are far from being understood. Here I will take decisive steps towards a causal understanding of these mechanisms by elucidating the role of functional interactions in the brain networks responsible for steering strategic, prosocial, and norm-compliant behavior. I will employ a unique multi-method approach that integrates computational modeling of social decisions with new combinations of multimodal neuroimaging and brain stimulation methods. Using EEG-fMRI, I will first identify spatio-temporal patterns of functional interactions between brain areas that correlate with social decision processes as identified by computational modeling of behavior in different economic games. In combined brain stimulation-fMRI studies, I will then attempt to affect – and in fact enhance – these social decision-making processes by modulating the identified brain network patterns with novel, targeted brain stimulation protocols and measuring the resulting effects on behavior and brain activity. Finally, I will examine whether the identified brain network mechanisms are indeed related to disturbed social decisions in two psychiatric illnesses characterized by maladaptive social behavior (post-traumatic stress disorder and autism spectrum disorder). My proposed work plan will generate a causal understanding of the brain network mechanisms that allow humans to control their social decisions, thereby elucidating a biological basis for individual differences in social behavior and paving the way for new perspectives on how disordered social behavior may be identified and hopefully remedied.
Max ERC Funding
1 999 991 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym CholeraIndex
Project Pathoecology of Vibrio cholerae to better understand cholera index cases in endemic areas
Researcher (PI) Melanie BLOKESCH
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Consolidator Grant (CoG), LS6, ERC-2016-COG
Summary Cholera is one of the oldest infectious diseases known and remains a major burden in many developing countries. The World Health Organization estimates that up to 4 million cases of cholera occur annually. The transmission of cholera by contaminated water, particularly under epidemic conditions, was first reported in the 19th century. However, early volunteer studies suggested that an incredibly high infectious dose (ID) is required to produce disease symptoms, in contrast to most other intestinal pathogens. Therefore, the mechanism of infection of index cases at the onset of an outbreak is unclear. This proposal aims to fill this knowledge gap by studying how the environmental lifestyle of the causative agent of the disease, the bacterium Vibrio cholerae, may prime the pathogen for intestinal colonization. We hypothesize that one of the natural niches of the bacterium (chitinous surfaces) fosters biofilm formation and provides a competitive advantage over co-colonizing bacteria. As an adaptive trait, passage of chitin-attached sessile V. cholerae through the acidic environment of the human stomach might be vastly facilitated compared to planktonic bacteria. Moreover, interbacterial warfare exerted by V. cholerae on these biotic surfaces may help the pathogen overcome the colonization barrier imposed by the human microbiota upon ingestion. The mechanism by which V. cholerae leaves the sessile lifestyle and the regulatory circuits involved in this process will also be investigated in this project. In summary, our goal is to elucidate the environmental community structures of V. cholerae that may enhance transmissibility from the ecosystem to humans in endemic areas resulting in the infection of index cases.
Summary
Cholera is one of the oldest infectious diseases known and remains a major burden in many developing countries. The World Health Organization estimates that up to 4 million cases of cholera occur annually. The transmission of cholera by contaminated water, particularly under epidemic conditions, was first reported in the 19th century. However, early volunteer studies suggested that an incredibly high infectious dose (ID) is required to produce disease symptoms, in contrast to most other intestinal pathogens. Therefore, the mechanism of infection of index cases at the onset of an outbreak is unclear. This proposal aims to fill this knowledge gap by studying how the environmental lifestyle of the causative agent of the disease, the bacterium Vibrio cholerae, may prime the pathogen for intestinal colonization. We hypothesize that one of the natural niches of the bacterium (chitinous surfaces) fosters biofilm formation and provides a competitive advantage over co-colonizing bacteria. As an adaptive trait, passage of chitin-attached sessile V. cholerae through the acidic environment of the human stomach might be vastly facilitated compared to planktonic bacteria. Moreover, interbacterial warfare exerted by V. cholerae on these biotic surfaces may help the pathogen overcome the colonization barrier imposed by the human microbiota upon ingestion. The mechanism by which V. cholerae leaves the sessile lifestyle and the regulatory circuits involved in this process will also be investigated in this project. In summary, our goal is to elucidate the environmental community structures of V. cholerae that may enhance transmissibility from the ecosystem to humans in endemic areas resulting in the infection of index cases.
Max ERC Funding
1 999 988 €
Duration
Start date: 2018-02-01, End date: 2023-07-31
Project acronym CHROCODYLE
Project Chromosomal Condensin Dynamics: From Local Loading to Global Architecture
Researcher (PI) Stephan GRUBER
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges.
Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex.
Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Summary
Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges.
Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex.
Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Max ERC Funding
1 999 599 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
