Project acronym AllOptHIPP
Project All-Optical Dissection of Hippocampal Circuits Using Voltage Imaging
Researcher (PI) Yoav Adam
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary The hippocampus is critical for the storage of episodic memories and has been extensively studied on its role in spatial memory. The hippocampus is also a central model for in vitro studies on the molecular, cellular and microcircuit basis for learning and memory. I propose to use a new technology that I developed to record and manipulate the membrane potential of multiple neurons, simultaneously, in behaving animals to reveal the mechanisms by which hippocampal circuits process spatial information. This research will bridge the gap between the in vitro mechanistic studies and the in vivo efforts to describe the spatial representations.
I first propose to employ the voltage imaging technology for detailed mechanistic studies of the function and plasticity of hippocampal microcircuits during place cell formation (Objective 1). To this end, we will combine voltage imaging with Optogenetics in head-fixed mice performing virtual navigation in familiar and novel environments. To expand to a ‘systems’ view on hippocampal plasticity, we will next establish a method for optical selection of single neurons based on their functional profile (Objective 2). We will use this technology to trace the long-range projections and the pre- and postsynaptic landscape of photo-selected CA1 neurons. In the last objective, we will combine both technologies to dissect the contribution of different entorhinal cell types (i.e. grid cells, border cells, and speed cells) to place cell formation in CA1 (objective 3). To this end, we will image the entorhinal cortex and photo-select cells based on their functional profiles. We will then image CA1 while manipulating the activity of the selected entorhinal cells. Our work will provide new discoveries on the mechanistic basis for spatial memory and will comprise a first step towards broader understanding of how the brain stores and retrieves episodic memories.
Summary
The hippocampus is critical for the storage of episodic memories and has been extensively studied on its role in spatial memory. The hippocampus is also a central model for in vitro studies on the molecular, cellular and microcircuit basis for learning and memory. I propose to use a new technology that I developed to record and manipulate the membrane potential of multiple neurons, simultaneously, in behaving animals to reveal the mechanisms by which hippocampal circuits process spatial information. This research will bridge the gap between the in vitro mechanistic studies and the in vivo efforts to describe the spatial representations.
I first propose to employ the voltage imaging technology for detailed mechanistic studies of the function and plasticity of hippocampal microcircuits during place cell formation (Objective 1). To this end, we will combine voltage imaging with Optogenetics in head-fixed mice performing virtual navigation in familiar and novel environments. To expand to a ‘systems’ view on hippocampal plasticity, we will next establish a method for optical selection of single neurons based on their functional profile (Objective 2). We will use this technology to trace the long-range projections and the pre- and postsynaptic landscape of photo-selected CA1 neurons. In the last objective, we will combine both technologies to dissect the contribution of different entorhinal cell types (i.e. grid cells, border cells, and speed cells) to place cell formation in CA1 (objective 3). To this end, we will image the entorhinal cortex and photo-select cells based on their functional profiles. We will then image CA1 while manipulating the activity of the selected entorhinal cells. Our work will provide new discoveries on the mechanistic basis for spatial memory and will comprise a first step towards broader understanding of how the brain stores and retrieves episodic memories.
Max ERC Funding
1 486 797 €
Duration
Start date: 2020-12-01, End date: 2025-11-30
Project acronym AxoMyoGlia
Project Spatio-functional cellular interplay in peripheral nerve diseases
Researcher (PI) Ruth Stassart
Host Institution (HI) UNIVERSITAET LEIPZIG
Country Germany
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Neuromuscular disorders belong to the most common but least treatable neurological conditions and are caused by defects in cell types that together build the neuromuscular unit – motoneurons and their axons, glial cells and myocytes. Clinically, neuromuscular diseases share an impairment of motor function and the intimate functional relationship of involved cell types suggests overlapping pathological mechanisms. As our current understanding is largely confined to locally isolated processes, the present AxoMyoGlia proposal will undertake the ambitious approach to elucidate the spatial dimensions of the molecular interplay among the key cellular players of the neuromuscular unit. By taking demyelinating peripheral neuropathies as a powerful model system, I aim at unravelling basic principles of how local glial impairment propagates malfunction within the neuromuscular unit, including potential remote axon and muscle feedback mechanisms. To this end, I will employ neuropathic mouse models and generate a holistic transcriptional cellular interactome of the diseased neuromuscular unit at single cell resolution level. With milli- to nanometer imaging precision, this interactome will be extended to the first visualization of the spatial relation between glial and axonal dysfunction along the entire longitudinal dimension of the nerve. In order to untangle local and distant causes from consequences, I will develop an innovative mouse model that will offer the unprecedented option to specifically induce and examine the global consequences of locally restricted glial neuropathy at any position in the neuromuscular system. With its pioneering multimodal approach to converge different areas of neuromuscular research, AxoMyoGlia aims at uncovering general pathological mechanisms at the interface of basic neuroscience and applied neurology - that will be highly relevant for therapeutic advance in neuromuscular diseases and related disorders of the central nervous system.
Summary
Neuromuscular disorders belong to the most common but least treatable neurological conditions and are caused by defects in cell types that together build the neuromuscular unit – motoneurons and their axons, glial cells and myocytes. Clinically, neuromuscular diseases share an impairment of motor function and the intimate functional relationship of involved cell types suggests overlapping pathological mechanisms. As our current understanding is largely confined to locally isolated processes, the present AxoMyoGlia proposal will undertake the ambitious approach to elucidate the spatial dimensions of the molecular interplay among the key cellular players of the neuromuscular unit. By taking demyelinating peripheral neuropathies as a powerful model system, I aim at unravelling basic principles of how local glial impairment propagates malfunction within the neuromuscular unit, including potential remote axon and muscle feedback mechanisms. To this end, I will employ neuropathic mouse models and generate a holistic transcriptional cellular interactome of the diseased neuromuscular unit at single cell resolution level. With milli- to nanometer imaging precision, this interactome will be extended to the first visualization of the spatial relation between glial and axonal dysfunction along the entire longitudinal dimension of the nerve. In order to untangle local and distant causes from consequences, I will develop an innovative mouse model that will offer the unprecedented option to specifically induce and examine the global consequences of locally restricted glial neuropathy at any position in the neuromuscular system. With its pioneering multimodal approach to converge different areas of neuromuscular research, AxoMyoGlia aims at uncovering general pathological mechanisms at the interface of basic neuroscience and applied neurology - that will be highly relevant for therapeutic advance in neuromuscular diseases and related disorders of the central nervous system.
Max ERC Funding
1 492 175 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym CERCODE
Project Cerebellar control of Cortical Development
Researcher (PI) Juan Antonio Moreno Bravo
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Country Spain
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary The cerebellum plays a critical role in motor function, but also in cognitive, and social behavioral development. It is proposed that the influence of the cerebellum in high-order processing is via modulatory effects on the cerebral cortex. Importantly, mounting evidences from clinical studies indicate that early cerebellar damage lead to wide range of changes in the structure and function of the developing cerebral cortex. This pathophysiological phenomenon is referred as “developmental diaschisis” and it suggests that the development of cerebral cortical areas is optimized by the guidance of cerebellar input. Thus, abnormalities in the developmental influence between these two brain regions might underlie the emergence of several neurodevelopmental disorders, such as autism spectrum disorders. Yet, the mechanisms by which the cerebellum is influencing the development and maturation of distant cortical circuits remain unknown.
Here, we will adopt a multidisciplinary and innovative approach to define the mechanisms by which the cerebellum influences the development of cortical areas. We hypothesize that these mechanisms are orchestrated by the thalamus, a key intermediate region connecting the cerebellum and the cortex. Therefore, a cerebellar malfunctioning might lead to alterations of cortical areas via thalamic reorganizations. Manipulating cerebellar early normal development and function offers us the possibility to shed light onto this issue. Thus, we will embryonically disturb the cerebello-thalamo-cortical output by anatomical, genetic and functional methods to determine the alterations in the development, organization, function and plasticity of the thalamocortical and cortical networks. The successful execution of this high-risk, high-impact research will provide insights on how the atypical cerebellar structure or function is involved in neurodevelopmental disorders.
Summary
The cerebellum plays a critical role in motor function, but also in cognitive, and social behavioral development. It is proposed that the influence of the cerebellum in high-order processing is via modulatory effects on the cerebral cortex. Importantly, mounting evidences from clinical studies indicate that early cerebellar damage lead to wide range of changes in the structure and function of the developing cerebral cortex. This pathophysiological phenomenon is referred as “developmental diaschisis” and it suggests that the development of cerebral cortical areas is optimized by the guidance of cerebellar input. Thus, abnormalities in the developmental influence between these two brain regions might underlie the emergence of several neurodevelopmental disorders, such as autism spectrum disorders. Yet, the mechanisms by which the cerebellum is influencing the development and maturation of distant cortical circuits remain unknown.
Here, we will adopt a multidisciplinary and innovative approach to define the mechanisms by which the cerebellum influences the development of cortical areas. We hypothesize that these mechanisms are orchestrated by the thalamus, a key intermediate region connecting the cerebellum and the cortex. Therefore, a cerebellar malfunctioning might lead to alterations of cortical areas via thalamic reorganizations. Manipulating cerebellar early normal development and function offers us the possibility to shed light onto this issue. Thus, we will embryonically disturb the cerebello-thalamo-cortical output by anatomical, genetic and functional methods to determine the alterations in the development, organization, function and plasticity of the thalamocortical and cortical networks. The successful execution of this high-risk, high-impact research will provide insights on how the atypical cerebellar structure or function is involved in neurodevelopmental disorders.
Max ERC Funding
1 499 709 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym DecOmPress
Project Decoding spatio-temporal omics in progressive neuroinflammation
Researcher (PI) Lucas Schirmer
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Country Germany
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Multiple sclerosis (MS) is a paradigmatic progressive neuroinflammatory disease characterized by multiple lesions across the entire central nervous system including both gray and white matter areas. Deconvoluting the spatio-temporal cellular and molecular landscape is therefore key to understanding underlying disease mechanisms and to develop cell-type specific therapies. The DecOmPress proposal is about integrative human and mouse single-cell genomic strategies to track-down reactive cellular states in compartmentalized progressive neuroinflammation. DecOmPress has two major research tracks (RTs).
RT1 is an MS tissue discovery pipeline utilizing single-nucleus RNA and open chromatin sequencing. RT1 is about developing novel integrative computational tools to process sequencing data from different anatomical lesion areas implementing a large multiplex single-nucleus genomic dataset from the anterior visual system. RT1 is also about decoding compartmentalized inflammation in meningeal versus perivascular tissue niches.
RT2 is a functional validation pipeline utilizing complex transgenic and disease mouse models as well as human organoids in combination with single-cell physiology and genomics. RT2 is about dissecting glial-intrinsic mechanisms at the chronically inflamed white matter lesion rim focusing on MS-specific oligodendrocyte and microglia subtypes. RT2 is also about decoding neuron subtype specific pathologies focusing on projection neurons and the contribution of local (meningeal) and distant (white matter tracts) inflammation and demyelination to cell-type specific neurodegeneration.
In summary, DecOmPress is a highly innovative and fully translational multidisciplinary proposal aiming at identifying novel cell-type specific disease mechanisms and therapeutic targets.
Summary
Multiple sclerosis (MS) is a paradigmatic progressive neuroinflammatory disease characterized by multiple lesions across the entire central nervous system including both gray and white matter areas. Deconvoluting the spatio-temporal cellular and molecular landscape is therefore key to understanding underlying disease mechanisms and to develop cell-type specific therapies. The DecOmPress proposal is about integrative human and mouse single-cell genomic strategies to track-down reactive cellular states in compartmentalized progressive neuroinflammation. DecOmPress has two major research tracks (RTs).
RT1 is an MS tissue discovery pipeline utilizing single-nucleus RNA and open chromatin sequencing. RT1 is about developing novel integrative computational tools to process sequencing data from different anatomical lesion areas implementing a large multiplex single-nucleus genomic dataset from the anterior visual system. RT1 is also about decoding compartmentalized inflammation in meningeal versus perivascular tissue niches.
RT2 is a functional validation pipeline utilizing complex transgenic and disease mouse models as well as human organoids in combination with single-cell physiology and genomics. RT2 is about dissecting glial-intrinsic mechanisms at the chronically inflamed white matter lesion rim focusing on MS-specific oligodendrocyte and microglia subtypes. RT2 is also about decoding neuron subtype specific pathologies focusing on projection neurons and the contribution of local (meningeal) and distant (white matter tracts) inflammation and demyelination to cell-type specific neurodegeneration.
In summary, DecOmPress is a highly innovative and fully translational multidisciplinary proposal aiming at identifying novel cell-type specific disease mechanisms and therapeutic targets.
Max ERC Funding
1 500 000 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym DstablizeMemory
Project Neural circuit mechanisms of memory destabilization
Researcher (PI) Johannes Felsenberg
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Memories can be rendered rewritable through a phenomenon called reconsolidation. The all-limiting step in this memory re-evaluation process is its initiation; the retrieval-dependent destabilization of the memory. However, the understanding of how a stable memory can be switched into a vulnerable but modifiable state is mostly in its infancy. Therefore, I aim to investigate the neural circuit mechanisms underlying retrieval-induced memory destabilization in the tractable fruit fly brain.
A prerequisite to investigate the neural mechanisms involved in destabilizing a memory is to know where the learned information is stored and to have access to the associated network. Olfactory memories in flies are stored in the mushroom body as changes between odor coding principle cells and valence coding output neurons. The cell specific genetic access to the 2500 neurons of each mushroom body allows to manipulate and monitor the activity of all components of the network in behaving animals. Recently I established a paradigm that allows to study the mechanisms underlying memory reconsolidation in this numerically simple brain structure. First results indicate that I have identified specific neurons which are crucial for destabilizing reward memory. Starting from these findings I will study the neural circuit mechanisms involved in memory destabilization.
I aim to generate an understanding of
1) the neural circuits underlying memory destabilization
2) how restrictive conditions gate reconsolidation
3) the role of targeted protein degradation in the destabilization of memory
The work will establish the first mechanistic insight into how memories are destabilized, how a destabilized memory is represented in the brain and how boundary conditions prevent the initiation of memory reconsolidation.
Summary
Memories can be rendered rewritable through a phenomenon called reconsolidation. The all-limiting step in this memory re-evaluation process is its initiation; the retrieval-dependent destabilization of the memory. However, the understanding of how a stable memory can be switched into a vulnerable but modifiable state is mostly in its infancy. Therefore, I aim to investigate the neural circuit mechanisms underlying retrieval-induced memory destabilization in the tractable fruit fly brain.
A prerequisite to investigate the neural mechanisms involved in destabilizing a memory is to know where the learned information is stored and to have access to the associated network. Olfactory memories in flies are stored in the mushroom body as changes between odor coding principle cells and valence coding output neurons. The cell specific genetic access to the 2500 neurons of each mushroom body allows to manipulate and monitor the activity of all components of the network in behaving animals. Recently I established a paradigm that allows to study the mechanisms underlying memory reconsolidation in this numerically simple brain structure. First results indicate that I have identified specific neurons which are crucial for destabilizing reward memory. Starting from these findings I will study the neural circuit mechanisms involved in memory destabilization.
I aim to generate an understanding of
1) the neural circuits underlying memory destabilization
2) how restrictive conditions gate reconsolidation
3) the role of targeted protein degradation in the destabilization of memory
The work will establish the first mechanistic insight into how memories are destabilized, how a destabilized memory is represented in the brain and how boundary conditions prevent the initiation of memory reconsolidation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2021-02-01, End date: 2026-01-31
Project acronym DYNAMIC_ENGRAM
Project Deciphering the enigma of memory persistence: how the brain stably stores information using dynamic networks and unstable neurons
Researcher (PI) Yaniv ZIV
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS5, ERC-2020-COG
Summary How does the brain store and retrieve information over time? The accepted notion that these processes rely on the neuronal ensembles that were active during learning is now challenged by findings by our lab and others that reveal that different neurons and networks than those that were active during learning support persistent memory. Most notably, we found that the long-term persistence of spatial memory is correlated with the degree to which neuronal activity is spatially informative, but not with the stability of the coding carried by individual neurons. These discoveries—obtained via novel imaging technologies that enable, for the first time, to track large populations of the same neurons over weeks—expose a fundamental gap in our understanding and highlight the need to reveal how neural codes across brain circuits, including the hippocampus, entorhinal cortex, and prefrontal cortex, change over the lifetime of a memory.
Here we propose to investigate the mechanisms that govern the reorganization of memory using innovative methods we recently developed for optical imaging, large-scale data analysis, and circuit manipulation. Key among them is our ability to simultaneously and longitudinally image in two related brain areas the activity of large neuronal populations in freely behaving mice. Using these new tools, we will elucidate the factors governing the circuit dynamics of memory representations (Aim 1); how such dynamics relate to the behavioral manifestation of memory (Aim 2); how hippocampal-cortical and cortical-cortical interactions change over weeks to support remote memory (Aim 3); and what mechanisms could underlie the transfer of learned information between neurons in a network (Aim 4).
Our approach will allow us to resolve how systems-level consolidation is realized at the neural code level, both within and across brain areas, and how a stable memory is maintained over the long term despite an ever-changing neuronal representation.
Summary
How does the brain store and retrieve information over time? The accepted notion that these processes rely on the neuronal ensembles that were active during learning is now challenged by findings by our lab and others that reveal that different neurons and networks than those that were active during learning support persistent memory. Most notably, we found that the long-term persistence of spatial memory is correlated with the degree to which neuronal activity is spatially informative, but not with the stability of the coding carried by individual neurons. These discoveries—obtained via novel imaging technologies that enable, for the first time, to track large populations of the same neurons over weeks—expose a fundamental gap in our understanding and highlight the need to reveal how neural codes across brain circuits, including the hippocampus, entorhinal cortex, and prefrontal cortex, change over the lifetime of a memory.
Here we propose to investigate the mechanisms that govern the reorganization of memory using innovative methods we recently developed for optical imaging, large-scale data analysis, and circuit manipulation. Key among them is our ability to simultaneously and longitudinally image in two related brain areas the activity of large neuronal populations in freely behaving mice. Using these new tools, we will elucidate the factors governing the circuit dynamics of memory representations (Aim 1); how such dynamics relate to the behavioral manifestation of memory (Aim 2); how hippocampal-cortical and cortical-cortical interactions change over weeks to support remote memory (Aim 3); and what mechanisms could underlie the transfer of learned information between neurons in a network (Aim 4).
Our approach will allow us to resolve how systems-level consolidation is realized at the neural code level, both within and across brain areas, and how a stable memory is maintained over the long term despite an ever-changing neuronal representation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-02-01, End date: 2026-01-31
Project acronym EXPECTPERCEPT
Project How our expectations can make us hallucinate: the neural mechanisms underlying perception
Researcher (PI) Peter Kok
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. In certain situations – namely when sensory signals are very weak or noisy and expectations are very strong – expectations can even induce hallucinations: seeing an expected stimulus despite its absence. However, the neural mechanisms by which the brain integrates sensory inputs and expectations, and thereby generates the contents of perception, have yet to be established. Previous work, including my own, has demonstrated that processing in the visual cortex is strongly modulated by prior expectations. However, perhaps surprisingly, previous studies have not yet explained how these modulations relate to subjective perception, leading to a lacuna in our knowledge of how the brain supports perception.
Here, I propose to study the neural mechanisms underlying subjective perception by using strong visual expectations to induce hallucinations in healthy human participants. I hypothesise that, upon presentation of a predictive cue (e.g., a siren), memory systems pre-activate templates of expected stimuli (an ambulance) in the deep layers of visual cortex, leading to biased processing of sensory inputs from the very moment they arrive. I will test this proposal by addressing three complimentary questions: 1) How do expectations filter perception? 2) What is the computational architecture underlying perceptual inference? 3) What is the neural source of expectations? I will combine psychophysical tasks probing participants’ perception with neuroimaging tools with exquisite spatial (high-field fMRI) and temporal (MEG) resolution to address these questions. The overarching aim of my research is to provide a mechanistic account of subjective perception. Ultimately, these insights may improve our understanding of clinical disorders characterised by aberrations in perception, such as psychosis.
Summary
The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. In certain situations – namely when sensory signals are very weak or noisy and expectations are very strong – expectations can even induce hallucinations: seeing an expected stimulus despite its absence. However, the neural mechanisms by which the brain integrates sensory inputs and expectations, and thereby generates the contents of perception, have yet to be established. Previous work, including my own, has demonstrated that processing in the visual cortex is strongly modulated by prior expectations. However, perhaps surprisingly, previous studies have not yet explained how these modulations relate to subjective perception, leading to a lacuna in our knowledge of how the brain supports perception.
Here, I propose to study the neural mechanisms underlying subjective perception by using strong visual expectations to induce hallucinations in healthy human participants. I hypothesise that, upon presentation of a predictive cue (e.g., a siren), memory systems pre-activate templates of expected stimuli (an ambulance) in the deep layers of visual cortex, leading to biased processing of sensory inputs from the very moment they arrive. I will test this proposal by addressing three complimentary questions: 1) How do expectations filter perception? 2) What is the computational architecture underlying perceptual inference? 3) What is the neural source of expectations? I will combine psychophysical tasks probing participants’ perception with neuroimaging tools with exquisite spatial (high-field fMRI) and temporal (MEG) resolution to address these questions. The overarching aim of my research is to provide a mechanistic account of subjective perception. Ultimately, these insights may improve our understanding of clinical disorders characterised by aberrations in perception, such as psychosis.
Max ERC Funding
1 484 575 €
Duration
Start date: 2021-08-01, End date: 2026-07-31
Project acronym FLEXPEPNET
Project Nervous system reprogramming by flexible neuropeptidergic networks
Researcher (PI) Isabel BEETS
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Country Belgium
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Animal brains are wired according to a series of remarkable genetic programs that have evolved over millions of years. Much of our behavior, however, is the product of experiences that happen to us on much shorter time scales. The ability of the nervous system to properly respond to aversive stimuli is crucial for animal well-being and survival. In many vertebrate sensory systems, persistent stimuli are coded by tonically active neural circuits. As opposed to phasic sensors that adapt rapidly, tonic neurons reliably convey stimulus intensity over long time periods and are essential for cues that need to hold attention, e.g. harmful stimuli. How persistent aversive stimuli are molecularly encoded and reprogram behavior remains elusive. Our working hypothesis is that aversive challenge recruits a network of neuropeptide signaling pathways that is sculpted by experience and mediates diverse acute and long-lasting behavioral responses.
We will test this hypothesis on the small and well-described oxygen-sensing circuit of C. elegans. Because neuropeptidergic networks are notoriously complex, such a highly controlled context for pioneering research on their involvement in tonic aversive signaling is preferable. First, my team will develop tools for the in vivo reporting of neuropeptide GPCR activation, establishing SPARK in a living animal, which will allow conceptual advancements with unprecedented detail. Pertinent questions we will then address include: ‘How do cellular networks respond to changes in neuropeptidergic network activities in an aversive signaling context?’; ‘What are behavioral implications of neuropeptidergic network activity upon aversive challenge?'; and ‘Do neuropeptidergic networks contribute to cross-modality?'
We expect that on the long term, this project will impact our understanding of how tonic peptidergic circuits influence and organize habituation, learning, forgetting and modus operandi of nervous systems in general.
Summary
Animal brains are wired according to a series of remarkable genetic programs that have evolved over millions of years. Much of our behavior, however, is the product of experiences that happen to us on much shorter time scales. The ability of the nervous system to properly respond to aversive stimuli is crucial for animal well-being and survival. In many vertebrate sensory systems, persistent stimuli are coded by tonically active neural circuits. As opposed to phasic sensors that adapt rapidly, tonic neurons reliably convey stimulus intensity over long time periods and are essential for cues that need to hold attention, e.g. harmful stimuli. How persistent aversive stimuli are molecularly encoded and reprogram behavior remains elusive. Our working hypothesis is that aversive challenge recruits a network of neuropeptide signaling pathways that is sculpted by experience and mediates diverse acute and long-lasting behavioral responses.
We will test this hypothesis on the small and well-described oxygen-sensing circuit of C. elegans. Because neuropeptidergic networks are notoriously complex, such a highly controlled context for pioneering research on their involvement in tonic aversive signaling is preferable. First, my team will develop tools for the in vivo reporting of neuropeptide GPCR activation, establishing SPARK in a living animal, which will allow conceptual advancements with unprecedented detail. Pertinent questions we will then address include: ‘How do cellular networks respond to changes in neuropeptidergic network activities in an aversive signaling context?’; ‘What are behavioral implications of neuropeptidergic network activity upon aversive challenge?'; and ‘Do neuropeptidergic networks contribute to cross-modality?'
We expect that on the long term, this project will impact our understanding of how tonic peptidergic circuits influence and organize habituation, learning, forgetting and modus operandi of nervous systems in general.
Max ERC Funding
1 559 808 €
Duration
Start date: 2021-01-01, End date: 2025-12-31
Project acronym GASSP
Project Genetic Architecture Of Sex Steroid-related Psychiatric Disorders
Researcher (PI) Arianna DI FLORIO
Host Institution (HI) CARDIFF UNIVERSITY
Country United Kingdom
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Psychiatric disorders associated with changes in female sex hormones are a major public health issue and represent a unique opportunity to study the complex interplay between gender, sex and mental states. GASSP aims to understand how genetic and environmental markers can help identify women at risk of psychiatric disorders in relation to the menstrual cycle, childbirth and transition to menopause and improve the current approach to diagnosis, prevention and treatment. It takes a ground-breaking approach across diagnoses and life stages, rather than focussing on the current diagnostic labels that have limited clinical and biological validity. It seeks to characterise the largest cohort to date of women with psychiatric disorders temporally related with changes in sex hormones by leveraging new technologies a) to identify and reach sufferers, making it easier for them to participate in research b) to conduct sophisticated analyses, integrating detailed longitudinal clinical and psycho-social information with aggregated genome-wide data and functional annotations. GASSP is the first molecular genetic study of the psychiatric sensitivity to sex hormone changes. It has the potential to contribute to the de-stigmatization of mental disorders related to female reproduction by providing evidence-based, easy-to-understand information to the public, and addressing the gender gap in psychiatry highlighted by the European Commission and the World Health Organization.
Summary
Psychiatric disorders associated with changes in female sex hormones are a major public health issue and represent a unique opportunity to study the complex interplay between gender, sex and mental states. GASSP aims to understand how genetic and environmental markers can help identify women at risk of psychiatric disorders in relation to the menstrual cycle, childbirth and transition to menopause and improve the current approach to diagnosis, prevention and treatment. It takes a ground-breaking approach across diagnoses and life stages, rather than focussing on the current diagnostic labels that have limited clinical and biological validity. It seeks to characterise the largest cohort to date of women with psychiatric disorders temporally related with changes in sex hormones by leveraging new technologies a) to identify and reach sufferers, making it easier for them to participate in research b) to conduct sophisticated analyses, integrating detailed longitudinal clinical and psycho-social information with aggregated genome-wide data and functional annotations. GASSP is the first molecular genetic study of the psychiatric sensitivity to sex hormone changes. It has the potential to contribute to the de-stigmatization of mental disorders related to female reproduction by providing evidence-based, easy-to-understand information to the public, and addressing the gender gap in psychiatry highlighted by the European Commission and the World Health Organization.
Max ERC Funding
1 499 961 €
Duration
Start date: 2021-12-01, End date: 2026-11-30
Project acronym HighMemory
Project Beyond classical conditioning: Hippocampal circuits in higher-order memory processes
Researcher (PI) Arnau Busquets Garcia
Host Institution (HI) FUNDACIO INSTITUT MAR D INVESTIGACIONS MEDIQUES IMIM
Country Spain
Call Details Starting Grant (StG), LS5, ERC-2020-STG
Summary Animals and humans adapt to changes in the environment through the encoding and storage of previous experiences. Although associative learning involving a reinforcer has been the major focus in the field of cognition, other forms of learning are gaining popularity as they are likely more relevant and frequent in human daily choices. Indeed, associations between non-reinforcing stimuli represent the most evolutionarily advanced way to increase the chances of predicting future events and adapting individuals’ behavior. Animals are also able to form these higher-order conditioning processes, but more research is needed to understand how the brain encode and store these complex cognitive processes. In this project, I propose to study the role of hippocampo-cortical circuits in higher-order conditioning processes. These processes explain why subjects are often repulsed or attracted by stimuli, which do not have intrinsic repellent or appealing value and they were never explicitly paired with negative or positive outcomes. A proposed explanation of these “ungrounded” aversion or attraction is that these stimuli were incidentally associated with other cues directly reinforced, through a process called mediated learning (ML). However, with increased incidental associations, the subjects acquire more information, allowing them to separate the real saliences of the different stimuli. Therefore, ML evolves into “reality testing”(RT), a behavioral process that has been even less studied. These processes involve multiple brain regions and are characterized by accessible phases, making them perfect models to study the circuit-level regulation of complex behavior. By using genetic, pharmacological, imaging and mouse behavioral approaches (sensory preconditioning), HighMemory proposes to characterize at macro- (brain regions), meso- (cell-types) and micro-scale (activity changes), the causal involvement of hippocampo-cortical projections in higher-order conditioning processes.
Summary
Animals and humans adapt to changes in the environment through the encoding and storage of previous experiences. Although associative learning involving a reinforcer has been the major focus in the field of cognition, other forms of learning are gaining popularity as they are likely more relevant and frequent in human daily choices. Indeed, associations between non-reinforcing stimuli represent the most evolutionarily advanced way to increase the chances of predicting future events and adapting individuals’ behavior. Animals are also able to form these higher-order conditioning processes, but more research is needed to understand how the brain encode and store these complex cognitive processes. In this project, I propose to study the role of hippocampo-cortical circuits in higher-order conditioning processes. These processes explain why subjects are often repulsed or attracted by stimuli, which do not have intrinsic repellent or appealing value and they were never explicitly paired with negative or positive outcomes. A proposed explanation of these “ungrounded” aversion or attraction is that these stimuli were incidentally associated with other cues directly reinforced, through a process called mediated learning (ML). However, with increased incidental associations, the subjects acquire more information, allowing them to separate the real saliences of the different stimuli. Therefore, ML evolves into “reality testing”(RT), a behavioral process that has been even less studied. These processes involve multiple brain regions and are characterized by accessible phases, making them perfect models to study the circuit-level regulation of complex behavior. By using genetic, pharmacological, imaging and mouse behavioral approaches (sensory preconditioning), HighMemory proposes to characterize at macro- (brain regions), meso- (cell-types) and micro-scale (activity changes), the causal involvement of hippocampo-cortical projections in higher-order conditioning processes.
Max ERC Funding
1 499 826 €
Duration
Start date: 2021-05-01, End date: 2026-04-30
