Project acronym ConCorND
Project Connectivity Correlate of Molecular Pathology in Neurodegeneration
Researcher (PI) Smita SAXENA
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Summary
Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym CYCLODE
Project Cyclical and Linear Timing Modes in Development
Researcher (PI) Helge GROSSHANS
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Advanced Grant (AdG), LS3, ERC-2016-ADG
Summary Organismal development requires proper timing of events such as cell fate choices, but the mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or ‘clocks’, that control recurring events such as vertebrate segmentation or nematode molting. Furthermore, it is unknown how cyclical timers are coordinated with the global, or linear, timing of development, e.g. to ensure an appropriate number of cyclical repeats. We propose to elucidate the components, wiring, and properties of a prototypic developmental clock by studying developmental timing in the roundworm C. elegans. We build on our recent discovery that nearly 20% of the worm’s transcriptome oscillates during larval development – an apparent manifestation of a clock that times the various recurring events that encompass each larval stage. Our aims are i) to identify components of this clock using genetic screens, ii) to gain insight into the system’s architecture and properties by employing specific perturbations such as food deprivation, and iii) to understand the coupling of this cyclic clock to the linear heterochronic timer through genetic manipulations. To achieve our ambitious goals, we will develop tools for mRNA sequencing of individual worms and for their developmental tracking and microchamber-based imaging. These important advances will increase temporal resolution, enhance signal-to-noise ratio, and achieve live tracking of oscillations in vivo. Our combination of genetic, genomic, imaging, and computational approaches will provide a detailed understanding of this clock, and biological timing mechanisms in general. As heterochronic genes and rhythmic gene expression are also important for controlling stem cell fates, we foresee that the results gained will additionally reveal regulatory mechanisms of stem cells, thus advancing our fundamental understanding of animal development and future applications in regenerative medicine.
Summary
Organismal development requires proper timing of events such as cell fate choices, but the mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or ‘clocks’, that control recurring events such as vertebrate segmentation or nematode molting. Furthermore, it is unknown how cyclical timers are coordinated with the global, or linear, timing of development, e.g. to ensure an appropriate number of cyclical repeats. We propose to elucidate the components, wiring, and properties of a prototypic developmental clock by studying developmental timing in the roundworm C. elegans. We build on our recent discovery that nearly 20% of the worm’s transcriptome oscillates during larval development – an apparent manifestation of a clock that times the various recurring events that encompass each larval stage. Our aims are i) to identify components of this clock using genetic screens, ii) to gain insight into the system’s architecture and properties by employing specific perturbations such as food deprivation, and iii) to understand the coupling of this cyclic clock to the linear heterochronic timer through genetic manipulations. To achieve our ambitious goals, we will develop tools for mRNA sequencing of individual worms and for their developmental tracking and microchamber-based imaging. These important advances will increase temporal resolution, enhance signal-to-noise ratio, and achieve live tracking of oscillations in vivo. Our combination of genetic, genomic, imaging, and computational approaches will provide a detailed understanding of this clock, and biological timing mechanisms in general. As heterochronic genes and rhythmic gene expression are also important for controlling stem cell fates, we foresee that the results gained will additionally reveal regulatory mechanisms of stem cells, thus advancing our fundamental understanding of animal development and future applications in regenerative medicine.
Max ERC Funding
2 358 625 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym MCircuits
Project Connectivity, plasticity and function of an olfactory memory circuit
Researcher (PI) Rainer FRIEDRICH
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary The brain accumulates knowledge by experience-driven modifications of neuronal connectivity and creates models of the world that enable intelligent behavior. It is thought that these processes are based on autoassociative mechanisms of circuit plasticity. However, direct tests of these fundamental concepts are difficult because they require dense reconstructions of neuronal wiring diagrams. We will dissect structural and functional mechanisms of autoassociative memory in telencephalic area Dp of adult zebrafish, the homologue of olfactory cortex. The small size of the zebrafish brain provides essential advantages for exhaustive measurements of neuronal activity and connectivity patterns. Key predictions of theoretical models will be examined by analyzing effects of odor discrimination learning on the dynamics and stability of odor representations in Dp. The underlying structural circuit modifications will be examined in the same brains by circuit reconstruction using serial block face scanning electron microscopy (SBEM). The dense reconstruction of neuronal ensembles responding to learned and novel odors will allow for advanced analyses of structure-function relationships that have not been possible so far. Odor stimulation in a virtual environment will be combined with optogenetic activation or silencing of neuromodulatory inputs to write and disrupt specific olfactory memories and to analyze the effects on behavior and connectivity. The underlying cellular mechanisms of synaptic plasticity and metaplasticity will be examined by electrophysiology, imaging and optogenetic approaches. Mutants will be used to assess effects of disease-related mutations on circuit structure, function and plasticity. These mechanistic analyses are guided by theoretical models, expected to generate direct insights into elementary computations underlying higher brain functions, and likely to uncover causal links between circuit connectivity, circuit function and behavior.
Summary
The brain accumulates knowledge by experience-driven modifications of neuronal connectivity and creates models of the world that enable intelligent behavior. It is thought that these processes are based on autoassociative mechanisms of circuit plasticity. However, direct tests of these fundamental concepts are difficult because they require dense reconstructions of neuronal wiring diagrams. We will dissect structural and functional mechanisms of autoassociative memory in telencephalic area Dp of adult zebrafish, the homologue of olfactory cortex. The small size of the zebrafish brain provides essential advantages for exhaustive measurements of neuronal activity and connectivity patterns. Key predictions of theoretical models will be examined by analyzing effects of odor discrimination learning on the dynamics and stability of odor representations in Dp. The underlying structural circuit modifications will be examined in the same brains by circuit reconstruction using serial block face scanning electron microscopy (SBEM). The dense reconstruction of neuronal ensembles responding to learned and novel odors will allow for advanced analyses of structure-function relationships that have not been possible so far. Odor stimulation in a virtual environment will be combined with optogenetic activation or silencing of neuromodulatory inputs to write and disrupt specific olfactory memories and to analyze the effects on behavior and connectivity. The underlying cellular mechanisms of synaptic plasticity and metaplasticity will be examined by electrophysiology, imaging and optogenetic approaches. Mutants will be used to assess effects of disease-related mutations on circuit structure, function and plasticity. These mechanistic analyses are guided by theoretical models, expected to generate direct insights into elementary computations underlying higher brain functions, and likely to uncover causal links between circuit connectivity, circuit function and behavior.
Max ERC Funding
2 495 839 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym MiTopMat
Project Microstructured Topological Materials: A novel route towards topological electronics
Researcher (PI) Philip MOLL
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Starting Grant (StG), PE3, ERC-2016-STG
Summary Topological semi-metals such as Cd3As2 or TaAs are characterized by two bands crossing at isolated points in momentum space and a linear electronic dispersion around these crossing points. This linear dispersion can be mapped onto the Dirac- or Weyl-Hamiltonian, describing relativistic massless fermions, and thus relativistic phenomena from high-energy physics may appear in these materials. For example, the chirality, χ=±1, is a conserved quantity for massless fermions, separating the electrons into two distinct chiral species. A new class of topological electronics has been proposed based on chirality imbalance and chiral currents taking the role of charge imbalance and charge currents in electronics. Such devices promise technological advances in speed, energy efficiency, and quantum coherent processes at elevated temperatures.
We will research the basic physical phenomena on which topological electronics is based: 1) The ability to interact electrically with the chiral states in a topological semi-metal is an essential prerequisite for their application. We will investigate whether currents in the Fermi arc surface states can be induced by charge currents and selectively detected by voltage measurements. 2) Weyl materials are more robust against defects and therefore of interest for industrial fabrication. We will experimentally test this topological protection in high-field transport experiments in a wide range of Weyl materials. 3) Recently, topological processes leading to fast, tuneable and efficient voltage inversion were predicted. We will investigate the phenomenon, fabricate and characterize such inverters, and assess their performance. MiTopMat thus aims to build the first prototype of a topological voltage inverter.
These goals are challenging but achievable: MiTopMat’s research plan is based on Focused Ion Beam microfabrication, which we have successfully shown to be a promising route to fabricate chiral devices.
Summary
Topological semi-metals such as Cd3As2 or TaAs are characterized by two bands crossing at isolated points in momentum space and a linear electronic dispersion around these crossing points. This linear dispersion can be mapped onto the Dirac- or Weyl-Hamiltonian, describing relativistic massless fermions, and thus relativistic phenomena from high-energy physics may appear in these materials. For example, the chirality, χ=±1, is a conserved quantity for massless fermions, separating the electrons into two distinct chiral species. A new class of topological electronics has been proposed based on chirality imbalance and chiral currents taking the role of charge imbalance and charge currents in electronics. Such devices promise technological advances in speed, energy efficiency, and quantum coherent processes at elevated temperatures.
We will research the basic physical phenomena on which topological electronics is based: 1) The ability to interact electrically with the chiral states in a topological semi-metal is an essential prerequisite for their application. We will investigate whether currents in the Fermi arc surface states can be induced by charge currents and selectively detected by voltage measurements. 2) Weyl materials are more robust against defects and therefore of interest for industrial fabrication. We will experimentally test this topological protection in high-field transport experiments in a wide range of Weyl materials. 3) Recently, topological processes leading to fast, tuneable and efficient voltage inversion were predicted. We will investigate the phenomenon, fabricate and characterize such inverters, and assess their performance. MiTopMat thus aims to build the first prototype of a topological voltage inverter.
These goals are challenging but achievable: MiTopMat’s research plan is based on Focused Ion Beam microfabrication, which we have successfully shown to be a promising route to fabricate chiral devices.
Max ERC Funding
1 836 070 €
Duration
Start date: 2017-12-01, End date: 2022-11-30
Project acronym MODMAT
Project Nonequilibrium dynamical mean-field theory: From models to materials
Researcher (PI) Philipp WERNER
Host Institution (HI) UNIVERSITE DE FRIBOURG
Call Details Consolidator Grant (CoG), PE3, ERC-2016-COG
Summary Pump-probe techniques are a powerful experimental tool for the study of strongly correlated electron systems. The strategy is to drive a material out of its equilibrium state by a laser pulse, and to measure the subsequent dynamics on the intrinsic timescale of the electron, spin and lattice degrees of freedom. This allows to disentangle competing low-energy processes along the time axis and to gain new insights into correlation phenomena. Pump-probe experiments have also shown that external stimulation can induce novel transient states, which raises the exciting prospect of nonequilibrium control of material properties.
The ab-initio simulation of correlated materials is challenging, and the prediction of a material's behavior under nonequilibrium conditions is an even more ambitious task. In the equilibrium context, a significant recent advance is the implementation of dynamical mean field theory (DMFT) schemes capable of treating dynamically screened interactions. These techniques have enabled the combination of the GW ab-initio method and DMFT in realistic contexts. Another recent development is the nonequilibrium extension of DMFT, which has been established as a flexible tool for the simulation of time-dependent phenomena in correlated lattice systems.
The goal of this research project is to combine these two recently developed computational techniques into a GW and nonequilibrium DMFT based ab-initio framework capable of delivering quantitative and material-specific predictions of the nonequilibrium properties of correlated compounds. The new formalism will be used to study photoinduced phasetransitions, unconventional superconductors with driven phonons, and strongly correlated devices such as Mott insulating solar cells.
Summary
Pump-probe techniques are a powerful experimental tool for the study of strongly correlated electron systems. The strategy is to drive a material out of its equilibrium state by a laser pulse, and to measure the subsequent dynamics on the intrinsic timescale of the electron, spin and lattice degrees of freedom. This allows to disentangle competing low-energy processes along the time axis and to gain new insights into correlation phenomena. Pump-probe experiments have also shown that external stimulation can induce novel transient states, which raises the exciting prospect of nonequilibrium control of material properties.
The ab-initio simulation of correlated materials is challenging, and the prediction of a material's behavior under nonequilibrium conditions is an even more ambitious task. In the equilibrium context, a significant recent advance is the implementation of dynamical mean field theory (DMFT) schemes capable of treating dynamically screened interactions. These techniques have enabled the combination of the GW ab-initio method and DMFT in realistic contexts. Another recent development is the nonequilibrium extension of DMFT, which has been established as a flexible tool for the simulation of time-dependent phenomena in correlated lattice systems.
The goal of this research project is to combine these two recently developed computational techniques into a GW and nonequilibrium DMFT based ab-initio framework capable of delivering quantitative and material-specific predictions of the nonequilibrium properties of correlated compounds. The new formalism will be used to study photoinduced phasetransitions, unconventional superconductors with driven phonons, and strongly correlated devices such as Mott insulating solar cells.
Max ERC Funding
1 854 321 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym MusEC
Project UNDERSTANDING THE METABOLIC CROSSTALK BETWEEN THE MUSCLE AND THE ENDOTHELIUM: IMPLICATIONS FOR EXERCISE TRAINING AND INSULIN RESISTANCE
Researcher (PI) Katrien DE BOCK
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS4, ERC-2016-STG
Summary Obesity has become a leading medical disorder, which is associated with life threatening conditions such as glucose intolerance, insulin resistance (IR) and type 2 diabetes (T2D). In the maintenance of glucose homeostasis, muscle is a critical organ and current health recommendations include regular physical activity as a cornerstone in the prevention and treatment of IR/T2D. The development of exercise mimetics has been proposed as a novel therapeutic strategy, but this has failed so far. This is because we still do not completely understand the etiology of glucose intolerance and how exercise improves glucose tolerance. In particular, angiogenesis – the growth of new blood vessels from existing ones – is an early adaptive event following exercise training, but the role of the muscle vasculature in the regulation of muscle metabolism and glucose tolerance has been largely overlooked.
In this project, I will investigate the metabolic crosstalk between the vasculature and the muscle to increase our understanding on how the endothelium contributes to muscle metabolism and glucose homeostasis. First, I will evaluate whether and how vessels need to reprogram their metabolism to promote angiogenesis following exercise training. Second, I will explore whether this metabolic reprogramming that results into enhanced angiogenesis is required for the muscle to allow training adaptations. I pose the novel and unexplored hypothesis that endothelial cells and the muscle intensely communicate to ensure optimal muscle function and to orchestrate muscle adaptations to exercise training via metabolic signaling. I will combine in vitro, ex vivo, and in vivo techniques using targeted and untargeted approaches to answer these exciting questions. Ultimately, I will investigate whether this communication is affected during the development of T2D. And if so, whether this interaction can be exploited to prevent IR/T2D.
Summary
Obesity has become a leading medical disorder, which is associated with life threatening conditions such as glucose intolerance, insulin resistance (IR) and type 2 diabetes (T2D). In the maintenance of glucose homeostasis, muscle is a critical organ and current health recommendations include regular physical activity as a cornerstone in the prevention and treatment of IR/T2D. The development of exercise mimetics has been proposed as a novel therapeutic strategy, but this has failed so far. This is because we still do not completely understand the etiology of glucose intolerance and how exercise improves glucose tolerance. In particular, angiogenesis – the growth of new blood vessels from existing ones – is an early adaptive event following exercise training, but the role of the muscle vasculature in the regulation of muscle metabolism and glucose tolerance has been largely overlooked.
In this project, I will investigate the metabolic crosstalk between the vasculature and the muscle to increase our understanding on how the endothelium contributes to muscle metabolism and glucose homeostasis. First, I will evaluate whether and how vessels need to reprogram their metabolism to promote angiogenesis following exercise training. Second, I will explore whether this metabolic reprogramming that results into enhanced angiogenesis is required for the muscle to allow training adaptations. I pose the novel and unexplored hypothesis that endothelial cells and the muscle intensely communicate to ensure optimal muscle function and to orchestrate muscle adaptations to exercise training via metabolic signaling. I will combine in vitro, ex vivo, and in vivo techniques using targeted and untargeted approaches to answer these exciting questions. Ultimately, I will investigate whether this communication is affected during the development of T2D. And if so, whether this interaction can be exploited to prevent IR/T2D.
Max ERC Funding
1 498 823 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym Opto-Sleep
Project All-optical deconstruction of thalamic control of sleep-wake states.
Researcher (PI) Antoine Roger Adamantidis
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary While the functions of sleep are still a matter of debate and may include memory consolidation, brain clearance, anabolism and plasticity, the neural substrates of sleep and wake states are the subject of intense study. Successive sleep-wake cycles rely on an appropriate balance between sleep-promoting nuclei of the brain located in the anterior hypothalamus and, arousal-promoting nuclei from the posterior hypothalamus and the brainstem. My laboratory identified different subsets of hypothalamic cells that controls wakefulness and rapid-eye movement (also called paradoxical) sleep using optogenetics in combination with high-density electrophysiology in freely-behaving mice. We further identified their connections with (and functional modulation of) other sleep-wake circuits throughout the brain. Although we and others have dissected important subcortical and cortical sleep-wake circuits in the brain, the precise mechanism bridging sub-cortical circuits to thalamic and cortical networks remains unclear.
I hypothesizes that the thalamus represents a hub that integrates sleep-wake inputs of both subcortical and cortical origin into stable sleep-wake states, through topographically distinct sub-cortical inputs and temporally precise circuit dynamics (spiking pattern, coherence).
To test this hypothesis, my experimental objectives are divided into three specific aims:
1) Identify the simultaneous cellular dynamics of thalamo-cortical network activity across sleep-wake states (Observational approach; Year 1-3)
2) Characterize the subcortical modulation of thalamic structures across sleep-wake states (Perturbational approach; Year 2-4)
3) Study the role of TRN/CMT circuits in sleep homeostasis and consciousness
(Functional approach; Year 4-5)
Completion of this project will provide a mechanistic perspective on sub-cortical, thalamo-cortical and cortical control of sleep-wake states, sleep homeostasis and consciousness in the mammalian brain.
Summary
While the functions of sleep are still a matter of debate and may include memory consolidation, brain clearance, anabolism and plasticity, the neural substrates of sleep and wake states are the subject of intense study. Successive sleep-wake cycles rely on an appropriate balance between sleep-promoting nuclei of the brain located in the anterior hypothalamus and, arousal-promoting nuclei from the posterior hypothalamus and the brainstem. My laboratory identified different subsets of hypothalamic cells that controls wakefulness and rapid-eye movement (also called paradoxical) sleep using optogenetics in combination with high-density electrophysiology in freely-behaving mice. We further identified their connections with (and functional modulation of) other sleep-wake circuits throughout the brain. Although we and others have dissected important subcortical and cortical sleep-wake circuits in the brain, the precise mechanism bridging sub-cortical circuits to thalamic and cortical networks remains unclear.
I hypothesizes that the thalamus represents a hub that integrates sleep-wake inputs of both subcortical and cortical origin into stable sleep-wake states, through topographically distinct sub-cortical inputs and temporally precise circuit dynamics (spiking pattern, coherence).
To test this hypothesis, my experimental objectives are divided into three specific aims:
1) Identify the simultaneous cellular dynamics of thalamo-cortical network activity across sleep-wake states (Observational approach; Year 1-3)
2) Characterize the subcortical modulation of thalamic structures across sleep-wake states (Perturbational approach; Year 2-4)
3) Study the role of TRN/CMT circuits in sleep homeostasis and consciousness
(Functional approach; Year 4-5)
Completion of this project will provide a mechanistic perspective on sub-cortical, thalamo-cortical and cortical control of sleep-wake states, sleep homeostasis and consciousness in the mammalian brain.
Max ERC Funding
1 915 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym ventralHippocampus
Project Neuronal circuits for emotions in the ventral CA1 hippocampus
Researcher (PI) Stéphane CIOCCHI
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary A fundamental objective in modern neurosciences is to understand the neural mechanisms of learning and memory in both healthy and pathological conditions. The hippocampus is a high-order cortical brain region important for emotions and cognition. The ventral subdivision of the hippocampus (anterior hippocampus in primates) is mostly involved in anxiety and contextual fear conditioning behaviours.
Pyramidal cells of the CA1 region of the hippocampus represent a main hippocampal output to numerous brains regions relevant for emotional and cognitive processes. The activity and timing of these CA1 pyramidal cells are controlled by a set of very diverse long-range afferent inputs and by local GABAergic interneurons. However, the function of afferent pathways to- and of local GABAergic interneurons in the ventral CA1 hippocampus during contextual fear conditioning and anxiety behaviours have not been investigated so far. We hypothesise that distinct sub-circuits in the ventral CA1 hippocampus differentially contribute to emotional behaviours by diverse and complementary neuronal and network mechanisms.
To test this hypothesis, we will use an innovative cross-level approach combining single-unit recordings of ventral CA1 GABAergic interneurons and of afferent brain regions to the ventral CA1 hippocampus, local field potential recordings, selective optogenetic strategies, cell-type-specific viral tracing, juxtacellular recording and labelling from ventral CA1 GABAergic interneurons, and behavioural paradigms in rodents. The originality of the proposal relies on identifying specific neuronal circuits and mechanisms in the ventral CA1 hippocampus to understand how normal and pathological brain function might arise at the behavioural level. Altogether, my research proposal aims at discovering logics of cortical computations during behaviour which may lead to translational applications for the clinics.
Summary
A fundamental objective in modern neurosciences is to understand the neural mechanisms of learning and memory in both healthy and pathological conditions. The hippocampus is a high-order cortical brain region important for emotions and cognition. The ventral subdivision of the hippocampus (anterior hippocampus in primates) is mostly involved in anxiety and contextual fear conditioning behaviours.
Pyramidal cells of the CA1 region of the hippocampus represent a main hippocampal output to numerous brains regions relevant for emotional and cognitive processes. The activity and timing of these CA1 pyramidal cells are controlled by a set of very diverse long-range afferent inputs and by local GABAergic interneurons. However, the function of afferent pathways to- and of local GABAergic interneurons in the ventral CA1 hippocampus during contextual fear conditioning and anxiety behaviours have not been investigated so far. We hypothesise that distinct sub-circuits in the ventral CA1 hippocampus differentially contribute to emotional behaviours by diverse and complementary neuronal and network mechanisms.
To test this hypothesis, we will use an innovative cross-level approach combining single-unit recordings of ventral CA1 GABAergic interneurons and of afferent brain regions to the ventral CA1 hippocampus, local field potential recordings, selective optogenetic strategies, cell-type-specific viral tracing, juxtacellular recording and labelling from ventral CA1 GABAergic interneurons, and behavioural paradigms in rodents. The originality of the proposal relies on identifying specific neuronal circuits and mechanisms in the ventral CA1 hippocampus to understand how normal and pathological brain function might arise at the behavioural level. Altogether, my research proposal aims at discovering logics of cortical computations during behaviour which may lead to translational applications for the clinics.
Max ERC Funding
1 493 736 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
