Project acronym ChronosAntibiotics
Project Exploring the bacterial cell cycle to re-sensitize antibiotic-resistant bacteria
Researcher (PI) MARIANA LUISA TOMAS GOMES DE PINHO
Host Institution (HI) UNIVERSIDADE NOVA DE LISBOA
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Summary
Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose:
(i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics.
(ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics.
(iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level.
Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.
Max ERC Funding
2 533 500 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym DYCOCIRC
Project Basal ganglia circuit mechanisms underlying dynamic cognitive behavior
Researcher (PI) Joseph PATON
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Summary
You’re faced with a difficult choice. What do you do? Most people will, either explicitly or implicitly, weigh the possible consequences their decision. This involves an internal journey through possible events. Its these kinds of dynamic processes and their mapping onto behavior that characterize higher brain function. And yet, their very internal nature is both what makes them of critical interest and so difficult to study. Here, we propose to study a simple, well-controlled decision-making behavior wherein mice have to generate a dynamic, internal representation of elapsed time in order to make choices that result in reward. We focus on frontal cortico-basal ganglia circuits and their dopaminergic inputs that together are broadly implicated in cognition and involved in the production of this particular behavior. We have demonstrated previously that striatal population dynamics and dopamine neuron activity both correlate with and exert control over animals’ judgments. Having identified key signals at multiple stages of the BG circuit related to this decision in rats and mice, my laboratory is now uniquely poised to dissect the circuit mechanisms by which such signals are generated and transformed into actions. Specifically, we will 1) Measure activity of specific cell types at multiple stages of the BG as mice judge duration. 2) Image and manipulate the activity of DA neurons while recording from neural populations in the BG to determine the relationship between neuromodulatory input, neural dynamics, and behavior. 3) Relate the activity of cortico-striatal inputs to striatal responses during behavior to understand the computational and circuit bases of striatal activity. These experiments promise to unlock deep mysteries regarding how animals free themselves from the immediacy of the current moment, learning, planning, and choosing their path toward a safer, more fruitful, and satisfying existence.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym FatTryp
Project Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for disease
Researcher (PI) Luisa FIGUEIREDO
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Background: The study of protozoan pathogens has been extensively explored often motivated to find suitable targets for new intervention strategies. However these studies have been mostly limited to those life-cycle stages that can be cultivated in vitro. Using a mouse model of African trypanosomiasis, we have recently discovered that the adipose tissue (fat) is a major reservoir for the extracellular protozoan Trypanosoma brucei and that, within this environment, parasites become phenotypically different from those in the blood. Our study exposed novel biology of the T. brucei life cycle, yet it remains unknown how parasites adapt to the fat and how parasite fat tropism affects disease.
Our first aim is to determine the molecular and cellular mechanisms underlying T. brucei fat tropism. We will perform a genetic screen in mice to identify key parasite genes required for establishing and maintaining chronic infection in the fat. Together with the information of the transcriptome and proteome, we will identify the mechanistic steps underlying parasite tissue-adaptation.
Our second aim is to identify the consequences of T. brucei fat tropism for the host and the importance for disease. We will first investigate if parasites can egress from the fat. We will also determine if parasites induce lipid breakdown in the host, leading to loss of fat mass. Finally, we will measure the impact of fat tropism in general traits of disease, including host survival and transmission potential.
Impact: This project represents a completely novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we will also improve the understanding of clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings will help elucidate disease mechanisms relevant to other infectious diseases.
Summary
Background: The study of protozoan pathogens has been extensively explored often motivated to find suitable targets for new intervention strategies. However these studies have been mostly limited to those life-cycle stages that can be cultivated in vitro. Using a mouse model of African trypanosomiasis, we have recently discovered that the adipose tissue (fat) is a major reservoir for the extracellular protozoan Trypanosoma brucei and that, within this environment, parasites become phenotypically different from those in the blood. Our study exposed novel biology of the T. brucei life cycle, yet it remains unknown how parasites adapt to the fat and how parasite fat tropism affects disease.
Our first aim is to determine the molecular and cellular mechanisms underlying T. brucei fat tropism. We will perform a genetic screen in mice to identify key parasite genes required for establishing and maintaining chronic infection in the fat. Together with the information of the transcriptome and proteome, we will identify the mechanistic steps underlying parasite tissue-adaptation.
Our second aim is to identify the consequences of T. brucei fat tropism for the host and the importance for disease. We will first investigate if parasites can egress from the fat. We will also determine if parasites induce lipid breakdown in the host, leading to loss of fat mass. Finally, we will measure the impact of fat tropism in general traits of disease, including host survival and transmission potential.
Impact: This project represents a completely novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we will also improve the understanding of clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings will help elucidate disease mechanisms relevant to other infectious diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym MagTendon
Project Magnetically Assisted Tissue Engineering Technologies for Tendon Regeneration
Researcher (PI) Maria Manuela ESTIMA GOMES
Host Institution (HI) UNIVERSIDADE DO MINHO
Call Details Consolidator Grant (CoG), PE8, ERC-2017-COG
Summary The poor healing ability of tendons, which play a critical role in the musculoskeletal system, as well as the limitations of currently used therapies have motivated tissue engineering (TE) strategies to develop living tendon substitutes. However, the limited knowledge on tendon development and healing processes has hindered the design of TE procedures that more closely recapitulate tendon morphogenesis. Extending beyond the state-of-the-art, MagTendon will explore conventional and innovative tools such as multimaterial 3 dimensional (3D) bioprinting to design magnetic responsive systems mimicking specific aspects of tendon tissue architecture, composition and biomechanical properties, which, combined with adequate stem cells, will render appropriate behavioural instructions to stimulate the regeneration of tendon tissue. Stem cell bioengineering approaches based on superparamagnetic nanoparticles (SPMNs), namely cell sorting, mechanoreceptors targeting and cell programming, will be used to unveil the cellular signalling pathways that trigger the tenogenic differentiation of the widely and easily obtained human adipose derived stem cells. Simultaneously, the 3D cell-laden magnetic system shall enable sophisticated 3D tissue models to unravel mechanisms behind tendon homeostasis and repair that will support the base knowledge to establish rational design criteria for the biofabrication of living tendon substitutes with the adequate signaling and structural cues to recapitulate tendon tissue developmental patterns. Therefore, the ground-breaking nature of the research proposed relies on the development of disruptive technological concepts for obtaining unique cell-laden 3D magnetically responsive systems that recapitulate key features of the native tissue and that can be further remotely modulated both in vitro and in vivo by the application of external magnetic stimuli, offering the prospect of tendon regeneration as opposed to simple tissue repair.
Summary
The poor healing ability of tendons, which play a critical role in the musculoskeletal system, as well as the limitations of currently used therapies have motivated tissue engineering (TE) strategies to develop living tendon substitutes. However, the limited knowledge on tendon development and healing processes has hindered the design of TE procedures that more closely recapitulate tendon morphogenesis. Extending beyond the state-of-the-art, MagTendon will explore conventional and innovative tools such as multimaterial 3 dimensional (3D) bioprinting to design magnetic responsive systems mimicking specific aspects of tendon tissue architecture, composition and biomechanical properties, which, combined with adequate stem cells, will render appropriate behavioural instructions to stimulate the regeneration of tendon tissue. Stem cell bioengineering approaches based on superparamagnetic nanoparticles (SPMNs), namely cell sorting, mechanoreceptors targeting and cell programming, will be used to unveil the cellular signalling pathways that trigger the tenogenic differentiation of the widely and easily obtained human adipose derived stem cells. Simultaneously, the 3D cell-laden magnetic system shall enable sophisticated 3D tissue models to unravel mechanisms behind tendon homeostasis and repair that will support the base knowledge to establish rational design criteria for the biofabrication of living tendon substitutes with the adequate signaling and structural cues to recapitulate tendon tissue developmental patterns. Therefore, the ground-breaking nature of the research proposed relies on the development of disruptive technological concepts for obtaining unique cell-laden 3D magnetically responsive systems that recapitulate key features of the native tissue and that can be further remotely modulated both in vitro and in vivo by the application of external magnetic stimuli, offering the prospect of tendon regeneration as opposed to simple tissue repair.
Max ERC Funding
1 999 854 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym NEUROFISH
Project Whole-brain circuits controlling visuomotor behavior
Researcher (PI) Michael Brian ORGER
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Understanding how our brains extract relevant features of sensory input to select and guide appropriate actions is a fundamental goal of neuroscience. Yet even relatively simple sensorimotor reflexes can depend on activity within complex networks of neurons that are distributed across the brain, presenting a challenge for traditional neuroscience approaches.
Our recent work has demonstrated the capacity to image neural activity with single cell resolution throughout the small transparent brain of behaving zebrafish. Here we will trace, from sensory input to motor output, the neural circuits that allow zebrafish to select and execute distinct swimming patterns in response to varying visual input. Through comprehensive whole-brain functional imaging in combination with optical and genetic circuit tracing, we aim to determine the principles on which these sensorimotor circuits are organised and reveal how activity dynamics unfold throughout the whole brain during behaviour.
We will take a systematic approach to this problem, based on a thorough quantitative analysis of swim kinematics and the sensory stimuli that drive them. We will: 1) Use whole-brain functional imaging of genetically defined neural populations to reveal the neural circuit organization and activity dynamics during visuomotor behaviour. 2) Establish how motor commands are encoded at the single-cell and population level by brainstem reticulospinal neurons, through imaging and ablation studies and 3) Systematically map the functional organisation of retinal inputs into the brain.
Taken together, these experiments will provide an unprecedented, single-cell resolution view of the organization of complete circuits that transform retinal inputs to motor outputs in the vertebrate brain.
Summary
Understanding how our brains extract relevant features of sensory input to select and guide appropriate actions is a fundamental goal of neuroscience. Yet even relatively simple sensorimotor reflexes can depend on activity within complex networks of neurons that are distributed across the brain, presenting a challenge for traditional neuroscience approaches.
Our recent work has demonstrated the capacity to image neural activity with single cell resolution throughout the small transparent brain of behaving zebrafish. Here we will trace, from sensory input to motor output, the neural circuits that allow zebrafish to select and execute distinct swimming patterns in response to varying visual input. Through comprehensive whole-brain functional imaging in combination with optical and genetic circuit tracing, we aim to determine the principles on which these sensorimotor circuits are organised and reveal how activity dynamics unfold throughout the whole brain during behaviour.
We will take a systematic approach to this problem, based on a thorough quantitative analysis of swim kinematics and the sensory stimuli that drive them. We will: 1) Use whole-brain functional imaging of genetically defined neural populations to reveal the neural circuit organization and activity dynamics during visuomotor behaviour. 2) Establish how motor commands are encoded at the single-cell and population level by brainstem reticulospinal neurons, through imaging and ablation studies and 3) Systematically map the functional organisation of retinal inputs into the brain.
Taken together, these experiments will provide an unprecedented, single-cell resolution view of the organization of complete circuits that transform retinal inputs to motor outputs in the vertebrate brain.
Max ERC Funding
1 694 063 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym TUgbOAT
Project Towards Unification of Algorithmic Tools
Researcher (PI) Piotr SANKOWSKI
Host Institution (HI) UNIWERSYTET WARSZAWSKI
Call Details Consolidator Grant (CoG), PE6, ERC-2017-COG
Summary Over last 50 years, extensive algorithmic research gave rise to a plethora of fundamental results. These results equipped us with increasingly better solutions to a number of core problems. However, many of these solutions are incomparable. The main reason for that is the fact that many cutting-edge algorithmic results are very specialized in their applicability. Often, they are limited to particular parameter range or require different assumptions.
A natural question arises: is it possible to get “one to rule them all” algorithm for some core problems such as matchings and maximum flow? In other words, can we unify our algorithms? That is, can we develop an algorithmic framework that enables us to combine a number of existing, only “conditionally” optimal, algorithms into a single all-around optimal solution? Such results would unify the landscape of algorithmic theory but would also greatly enhance the impact of these cutting-edge developments on the real world. After all, algorithms and data structures are the basic building blocks of every computer program. However, currently using cutting-edge algorithms in an optimal way requires extensive expertise and thorough understanding of both the underlying implementation and the characteristics of the input data.
Hence, the need for such unified solutions seems to be critical from both theoretical and practical perspective. However, obtaining such algorithmic unification poses serious theoretical challenges. We believe that some of the recent advances in algorithms provide us with an opportunity to make serious progress towards solving these challenges in the context of several fundamental algorithmic problems. This project should be seen as the start of such a systematic study of unification of algorithmic tools with the aim to remove the need to “under the hood” while still guaranteeing an optimal performance independently of the particular usage case.
Summary
Over last 50 years, extensive algorithmic research gave rise to a plethora of fundamental results. These results equipped us with increasingly better solutions to a number of core problems. However, many of these solutions are incomparable. The main reason for that is the fact that many cutting-edge algorithmic results are very specialized in their applicability. Often, they are limited to particular parameter range or require different assumptions.
A natural question arises: is it possible to get “one to rule them all” algorithm for some core problems such as matchings and maximum flow? In other words, can we unify our algorithms? That is, can we develop an algorithmic framework that enables us to combine a number of existing, only “conditionally” optimal, algorithms into a single all-around optimal solution? Such results would unify the landscape of algorithmic theory but would also greatly enhance the impact of these cutting-edge developments on the real world. After all, algorithms and data structures are the basic building blocks of every computer program. However, currently using cutting-edge algorithms in an optimal way requires extensive expertise and thorough understanding of both the underlying implementation and the characteristics of the input data.
Hence, the need for such unified solutions seems to be critical from both theoretical and practical perspective. However, obtaining such algorithmic unification poses serious theoretical challenges. We believe that some of the recent advances in algorithms provide us with an opportunity to make serious progress towards solving these challenges in the context of several fundamental algorithmic problems. This project should be seen as the start of such a systematic study of unification of algorithmic tools with the aim to remove the need to “under the hood” while still guaranteeing an optimal performance independently of the particular usage case.
Max ERC Funding
1 510 800 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym WOLBAKIAN
Project Functional genetics of Wolbachia proliferation and protection to viruses
Researcher (PI) Luis Manuel VALLA TEIXEIRA
Host Institution (HI) FUNDACAO CALOUSTE GULBENKIAN
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary Wolbachia are arguably the most prevalent intracellular bacteria in animals, infecting filarial nematodes and up to 66% of arthropod species. Wolbachia are maternally transmitted and can induce a large range of strong phenotypes on their hosts. However, very little is known on how they induce these phenotypes and how they interact with the host at the molecular level. One main difficulty with this system is that Wolbachia have been genetically intractable. We will study how Wolbachia confers protection to viruses, a phenomenon that is currently being applied to fight dengue and Zika viruses. We also aim at understanding how these endosymbiont titres are regulated, a crucial aspect of their biology. We will identify host and Wolbachia genes that regulate these processes by performing classical genetic screens in Drosophila and develop a new method to perform a forward genetic screen in Wolbachia. Our previous analysis of natural variants of Wolbachia will also be extended in order to identify alleles associated with differential growth and antiviral protection. We will characterize candidate Wolbachia genes, from the previous analysis and current results in the lab, by performing a new method to obtain loss-of-function mutants in target Wolbachia genes. We will also focus on putative effector proteins of Wolbachia with the purpose of identifying cellular location, induced phenotypes, and host interacting proteins. Drosophila genes will be characterized by classical genetic methods in this model organism. The identification and characterization of Wolbachia and host genes involved in antiviral protection and Wolbachia proliferation will provide key insights to these basic biological problems. Moreover, the knowledge generated and new Wolbachia variants may have an application in the fight against arboviruses transmitted by mosquitoes and human diseases caused by filarial nematodes.
Summary
Wolbachia are arguably the most prevalent intracellular bacteria in animals, infecting filarial nematodes and up to 66% of arthropod species. Wolbachia are maternally transmitted and can induce a large range of strong phenotypes on their hosts. However, very little is known on how they induce these phenotypes and how they interact with the host at the molecular level. One main difficulty with this system is that Wolbachia have been genetically intractable. We will study how Wolbachia confers protection to viruses, a phenomenon that is currently being applied to fight dengue and Zika viruses. We also aim at understanding how these endosymbiont titres are regulated, a crucial aspect of their biology. We will identify host and Wolbachia genes that regulate these processes by performing classical genetic screens in Drosophila and develop a new method to perform a forward genetic screen in Wolbachia. Our previous analysis of natural variants of Wolbachia will also be extended in order to identify alleles associated with differential growth and antiviral protection. We will characterize candidate Wolbachia genes, from the previous analysis and current results in the lab, by performing a new method to obtain loss-of-function mutants in target Wolbachia genes. We will also focus on putative effector proteins of Wolbachia with the purpose of identifying cellular location, induced phenotypes, and host interacting proteins. Drosophila genes will be characterized by classical genetic methods in this model organism. The identification and characterization of Wolbachia and host genes involved in antiviral protection and Wolbachia proliferation will provide key insights to these basic biological problems. Moreover, the knowledge generated and new Wolbachia variants may have an application in the fight against arboviruses transmitted by mosquitoes and human diseases caused by filarial nematodes.
Max ERC Funding
1 999 500 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym YinYang
Project Hypothalamic circuits for the selection of defensive and mating behavior in females
Researcher (PI) Susana LIMA
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Social interactions can take different courses depending on the internal state of the participants. For instance, a sexually receptive female mouse will allow a male’s attempt to mount her, but a non-receptive female will fight or flee the same male. Here, we propose to determine how neuronal circuits in the female mouse brain support flexible, state-dependent interactions with male conspecifics. It is known that female receptivity depends on the ventrolateral region of the ventromedial hypothalamus. Within this region there is a population of neurons that expresses receptors for the sex hormone progesterone (PR+ neurons), whose levels cycle with reproductive state. In pilot experiments, we found that PR+ neurons are not homogeneous: some respond during receptive behaviors but others respond during defensive or aggressive behaviors. Our main objective is to determine how female hypothalamic PR+ neurons participate in state-dependent behavioral responses to males. Our hypothesis is that two subpopulations of PR+ neurons are differentially modulated by the reproductive cycle and that each sub-population activates a different downstream circuit, one specialized for receptive and the other for defensive behaviors. Our specific aims are to: (1) characterize the functional selectivity of individual female PR+ neurons across the reproductive cycle; (2) map the connectivity of PR+ neurons to their output targets; (3) test the impact of different PR+ output pathways by genetically activating and silencing them; and (4) determine how reproductive hormones modulate the synaptic and intrinsic functional properties of PR+ neurons. These studies will elucidate the neuronal circuit mechanisms of a biologically essential female behavior. More broadly, this work will reveal mechanisms by which neuronal circuits can support flexible state-dependent adaptive behaviors.
Summary
Social interactions can take different courses depending on the internal state of the participants. For instance, a sexually receptive female mouse will allow a male’s attempt to mount her, but a non-receptive female will fight or flee the same male. Here, we propose to determine how neuronal circuits in the female mouse brain support flexible, state-dependent interactions with male conspecifics. It is known that female receptivity depends on the ventrolateral region of the ventromedial hypothalamus. Within this region there is a population of neurons that expresses receptors for the sex hormone progesterone (PR+ neurons), whose levels cycle with reproductive state. In pilot experiments, we found that PR+ neurons are not homogeneous: some respond during receptive behaviors but others respond during defensive or aggressive behaviors. Our main objective is to determine how female hypothalamic PR+ neurons participate in state-dependent behavioral responses to males. Our hypothesis is that two subpopulations of PR+ neurons are differentially modulated by the reproductive cycle and that each sub-population activates a different downstream circuit, one specialized for receptive and the other for defensive behaviors. Our specific aims are to: (1) characterize the functional selectivity of individual female PR+ neurons across the reproductive cycle; (2) map the connectivity of PR+ neurons to their output targets; (3) test the impact of different PR+ output pathways by genetically activating and silencing them; and (4) determine how reproductive hormones modulate the synaptic and intrinsic functional properties of PR+ neurons. These studies will elucidate the neuronal circuit mechanisms of a biologically essential female behavior. More broadly, this work will reveal mechanisms by which neuronal circuits can support flexible state-dependent adaptive behaviors.
Max ERC Funding
1 952 188 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
