Project acronym CORTEXFOLDING
Project Understanding the development and function of cerebral cortex folding
Researcher (PI) Victor Borrell Franco
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary The mammalian cerebral cortex was subject to a dramatic expansion in surface area during evolution. This process is recapitulated during development and is accompanied by folding of the cortical sheet, which allows fitting a large cortical surface within a limited cranial volume. A loss of cortical folds is linked to severe intellectual impairment in humans, so cortical folding is believed to be crucial for brain function. However, developmental mechanisms responsible for cortical folding, and the influence of this on cortical function, remain largely unknown. The goal of this proposal is to understand the genetic and cellular mechanisms that control the developmental expansion and folding of the cerebral cortex, and what is the impact of these processes on its functional organization. Human studies have identified genes essential for the proper folding of the human cerebral cortex. Genetic manipulations in mice have unraveled specific functions for some of those genes in the development of the cerebral cortex. But because the mouse cerebral cortex does not fold naturally, the mechanisms of cortical expansion and folding in larger brains remain unknown. We will study these mechanisms on ferret, an ideal model with a naturally folded cerebral cortex. We will combine the advantages of ferrets with cell biology, genetics and next-generation transcriptomics, together with state-of-the-art in vivo, in vitro and in silico approaches, including in vivo imaging of functional columnar maps. The successful execution of this project will provide insights into developmental and genetic risk factors for anomalies in human cortical topology, and into mechanisms responsible for the early formation of cortical functional maps.
Summary
The mammalian cerebral cortex was subject to a dramatic expansion in surface area during evolution. This process is recapitulated during development and is accompanied by folding of the cortical sheet, which allows fitting a large cortical surface within a limited cranial volume. A loss of cortical folds is linked to severe intellectual impairment in humans, so cortical folding is believed to be crucial for brain function. However, developmental mechanisms responsible for cortical folding, and the influence of this on cortical function, remain largely unknown. The goal of this proposal is to understand the genetic and cellular mechanisms that control the developmental expansion and folding of the cerebral cortex, and what is the impact of these processes on its functional organization. Human studies have identified genes essential for the proper folding of the human cerebral cortex. Genetic manipulations in mice have unraveled specific functions for some of those genes in the development of the cerebral cortex. But because the mouse cerebral cortex does not fold naturally, the mechanisms of cortical expansion and folding in larger brains remain unknown. We will study these mechanisms on ferret, an ideal model with a naturally folded cerebral cortex. We will combine the advantages of ferrets with cell biology, genetics and next-generation transcriptomics, together with state-of-the-art in vivo, in vitro and in silico approaches, including in vivo imaging of functional columnar maps. The successful execution of this project will provide insights into developmental and genetic risk factors for anomalies in human cortical topology, and into mechanisms responsible for the early formation of cortical functional maps.
Max ERC Funding
1 701 116 €
Duration
Start date: 2013-01-01, End date: 2018-06-30
Project acronym MULTICELLGENOME
Project A comparative genomic analysis into the origin of metazoan multicellularity
Researcher (PI) Inaki Ruiz Trillo
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The emergence of multicellular organisms from single-celled ancestors is one of the most profound evolutionary steps in life’s history. However, and despite its importance, little is known about this pivotal evolutionary event. Interestingly, the emergence of multicellular organisms has occurred several times independently within the eukaryotes, such as in animals, fungi and plants. In this context, the super-group known as the Opisthokonts offers a unique evolutionary window to investigate the unicell-to-multicell transition because it comprises two multicellular eukaryotic kingdoms (Animals and Fungi) and several single-celled lineages. The goal of this project is to perform a comparative genomic analysis to further investigate into the origin of multicellularity within metazoans. Although genomic and functional studies are currently being performed in basal and derived metazoans, among the animal unicellular ancestors, choanoflagellates remain the only lineage to be extensively studied. This project aims to fill this gap by providing a genomic and molecular investigation into two additional unicellular lineages recently shown to be closely related to animals: Capsaspora owczarzaki and the ichthyosporean Sphaeroforma arctica. Thus, the specific goals of this project are: 1) to analyze the complete genome sequence of the unicellular opisthokonts Capsaspora and Sphaeroforma; and 2) to launch a new functional genomics platform of both Capsaspora and Sphaeroforma, in where to elucidate the “ancestral function” of genes relevant to multicellularity. A broad range of researchers (including the “evo-devo” community, eukaryotic microbiologists and molecular evolutionists) will benefit from the data generated within this project. Surely, this research will not only largely improve our understanding of a major biological question (the origin/s of multicellularity) but will also provide an evolutionary insight into the evolution of key proteins relevant to human health.
Summary
The emergence of multicellular organisms from single-celled ancestors is one of the most profound evolutionary steps in life’s history. However, and despite its importance, little is known about this pivotal evolutionary event. Interestingly, the emergence of multicellular organisms has occurred several times independently within the eukaryotes, such as in animals, fungi and plants. In this context, the super-group known as the Opisthokonts offers a unique evolutionary window to investigate the unicell-to-multicell transition because it comprises two multicellular eukaryotic kingdoms (Animals and Fungi) and several single-celled lineages. The goal of this project is to perform a comparative genomic analysis to further investigate into the origin of multicellularity within metazoans. Although genomic and functional studies are currently being performed in basal and derived metazoans, among the animal unicellular ancestors, choanoflagellates remain the only lineage to be extensively studied. This project aims to fill this gap by providing a genomic and molecular investigation into two additional unicellular lineages recently shown to be closely related to animals: Capsaspora owczarzaki and the ichthyosporean Sphaeroforma arctica. Thus, the specific goals of this project are: 1) to analyze the complete genome sequence of the unicellular opisthokonts Capsaspora and Sphaeroforma; and 2) to launch a new functional genomics platform of both Capsaspora and Sphaeroforma, in where to elucidate the “ancestral function” of genes relevant to multicellularity. A broad range of researchers (including the “evo-devo” community, eukaryotic microbiologists and molecular evolutionists) will benefit from the data generated within this project. Surely, this research will not only largely improve our understanding of a major biological question (the origin/s of multicellularity) but will also provide an evolutionary insight into the evolution of key proteins relevant to human health.
Max ERC Funding
1 211 275 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym MyeRIBO
Project Deconstructing the Translational Control of Myelination by Specialized Ribosomes
Researcher (PI) Ashwin WOODHOO
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Call Details Consolidator Grant (CoG), LS5, ERC-2019-COG
Summary The myelin sheath is essential for neuronal function and health: myelinating glial cells speed up propagation of axonal potentials, fuel the energetic demands and regulate the ionic environment of neurons. Lesions to the myelin sheath thus result in devastating neurological disorders that include multiple sclerosis, diabetic neuropathy and Charcot-Marie-Tooth disease. Myelination involves a striking expansion of the glial cell membrane that relies on an exceptional increase in protein and lipid synthesis rates. Decades of dedicated research has uncovered a complex transcriptional program that drives this process, whereas translational control mechanisms, on the other hand, have received little attention. There is emerging evidence, enabled by modern techniques, that ribosomes, typically viewed as invariant, passive molecular machines, may instead be heterogeneous in composition, with particular ribosomal components having a ‘specialized’ regulatory capacity for preferential translation of specific mRNAs. In MyeRIBO, I propose that translation control by specialized ribosomes is a novel layer of regulation that shapes the proteome of the myelinating glial cell. I will exploit advances in cryo-EM and quantitative proteomics analyses to discover the nature and diversity of ribosomes in myelinating cells, employ genome-wide ribosome profiling to obtain mechanistic insights into selective mRNA translation by heterogeneous ribosomes, and generate genetic mouse models to determine the functional consequences of this specialization for myelination in vivo. Notably, I will study the implication of this mechanism in pathogenesis of injury-induced demyelination and diabetic neuropathy, and evaluate the targeting of specialized ribosomal components as a preclinical strategy. MyeRIBO will push further the boundaries of our current understanding of the molecular control of myelination, which could have a profound impact for understanding neural development and myelin disorders.
Summary
The myelin sheath is essential for neuronal function and health: myelinating glial cells speed up propagation of axonal potentials, fuel the energetic demands and regulate the ionic environment of neurons. Lesions to the myelin sheath thus result in devastating neurological disorders that include multiple sclerosis, diabetic neuropathy and Charcot-Marie-Tooth disease. Myelination involves a striking expansion of the glial cell membrane that relies on an exceptional increase in protein and lipid synthesis rates. Decades of dedicated research has uncovered a complex transcriptional program that drives this process, whereas translational control mechanisms, on the other hand, have received little attention. There is emerging evidence, enabled by modern techniques, that ribosomes, typically viewed as invariant, passive molecular machines, may instead be heterogeneous in composition, with particular ribosomal components having a ‘specialized’ regulatory capacity for preferential translation of specific mRNAs. In MyeRIBO, I propose that translation control by specialized ribosomes is a novel layer of regulation that shapes the proteome of the myelinating glial cell. I will exploit advances in cryo-EM and quantitative proteomics analyses to discover the nature and diversity of ribosomes in myelinating cells, employ genome-wide ribosome profiling to obtain mechanistic insights into selective mRNA translation by heterogeneous ribosomes, and generate genetic mouse models to determine the functional consequences of this specialization for myelination in vivo. Notably, I will study the implication of this mechanism in pathogenesis of injury-induced demyelination and diabetic neuropathy, and evaluate the targeting of specialized ribosomal components as a preclinical strategy. MyeRIBO will push further the boundaries of our current understanding of the molecular control of myelination, which could have a profound impact for understanding neural development and myelin disorders.
Max ERC Funding
1 874 996 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym NANOPDICS
Project Optoelectrical Dynamics of Ion channel Activation in Calcium Nanodomains
Researcher (PI) Teresa Giraldez Fernandez
Host Institution (HI) UNIVERSIDAD DE LA LAGUNA
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary In neurons, sites of Ca2+ influx and Ca2+ sensors are located within 20-50 nm, in subcellular “Ca2+ nanodomains”. Such tight coupling is crucial for the functional properties of synapses and neuronal excitability. Two key players act together in nanodomains, coupling Ca2+ signal to membrane potential: the voltage-dependent Ca2+ channels (VDCC) and the large conductance Ca2+ and voltage-gated K+ channels (BK). BK channels are characterized by synergistic activation by Ca2+ and membrane depolarization, but the complex molecular mechanism underlying channel function is not adequately understood. Information about the pore region, voltage sensing domain or isolated intracellular domains has been obtained separately using electrophysiology, biochemistry and crystallography. Nevertheless, the specialized behavior of this channel must be studied in the whole protein complex at the membrane in order to determine the complete range of structures and movements critical to its in vivo function. Using a combination of genetics, electrophysiology and spectroscopy, our group has measured for the first time the structural rearrangements accompanying whole BK channel activation at the membrane. From this unique position, our first goal is to fully determine the real time structural dynamics underlying the molecular coupling of Ca2+, voltage and activation of BK channels in the membrane environment, its regulation by accessory subunits and channel effectors.
BK subcellular localization and role in Ca2+ nanodomains make these channels perfect candidates as reporters of local changes in [Ca2+] restricted to specific nanodomains close to the neuronal membrane. In our laboratory we have created fluorescent variants of the channel that report BK activity induced by Ca2+ binding, or Ca2+ binding and voltage. Our second aim in this proposal is to optimize and deploy this novel optoelectrical reporters to study physiologically relevant Ca2+-induced processes both in cellular and animal mode
Summary
In neurons, sites of Ca2+ influx and Ca2+ sensors are located within 20-50 nm, in subcellular “Ca2+ nanodomains”. Such tight coupling is crucial for the functional properties of synapses and neuronal excitability. Two key players act together in nanodomains, coupling Ca2+ signal to membrane potential: the voltage-dependent Ca2+ channels (VDCC) and the large conductance Ca2+ and voltage-gated K+ channels (BK). BK channels are characterized by synergistic activation by Ca2+ and membrane depolarization, but the complex molecular mechanism underlying channel function is not adequately understood. Information about the pore region, voltage sensing domain or isolated intracellular domains has been obtained separately using electrophysiology, biochemistry and crystallography. Nevertheless, the specialized behavior of this channel must be studied in the whole protein complex at the membrane in order to determine the complete range of structures and movements critical to its in vivo function. Using a combination of genetics, electrophysiology and spectroscopy, our group has measured for the first time the structural rearrangements accompanying whole BK channel activation at the membrane. From this unique position, our first goal is to fully determine the real time structural dynamics underlying the molecular coupling of Ca2+, voltage and activation of BK channels in the membrane environment, its regulation by accessory subunits and channel effectors.
BK subcellular localization and role in Ca2+ nanodomains make these channels perfect candidates as reporters of local changes in [Ca2+] restricted to specific nanodomains close to the neuronal membrane. In our laboratory we have created fluorescent variants of the channel that report BK activity induced by Ca2+ binding, or Ca2+ binding and voltage. Our second aim in this proposal is to optimize and deploy this novel optoelectrical reporters to study physiologically relevant Ca2+-induced processes both in cellular and animal mode
Max ERC Funding
1 999 742 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym NEUROMITO
Project Elucidating Neuronal Susceptibility to Mitochondrial Disease
Researcher (PI) Albert Quintana
Host Institution (HI) UNIVERSIDAD AUTONOMA DE BARCELONA
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary Mitochondria generate most of the energy cells require to function. Deficits in the mitochondrial energy-generating machinery affect 1:5,000 children and cause progressive, debilitating, and usually fatal pathologies collectively known as primary mitochondrial disease. To date, there is no cure for mitochondrial disease and existing treatments are highly ineffective and mostly palliative. High-energy-requiring cells, such as neurons, are especially affected in mitochondrial disease. However, not all neuronal populations are equally affected. Furthermore, the molecular determinants of neuronal vulnerability to mitochondrial disease have not been adequately elucidated, representing a challenge for the development of efficient treatments for these pathologies. To improve on current knowledge on mitochondrial disease and to provide better therapeutic targets, this project focuses on developing ground-breaking mouse genetics and molecular biology tools that will allow the identification and dissection of the molecular determinants of neuronal vulnerability in mitochondrial disease with unprecedented definition. We will develop novel techniques to isolate both the mitochondrial and cytosolic translatome by using ribosomal tagging in vivo as well as to assess intact mitochondrial function with cell-type specificity and temporal resolution. These novel approaches will have a high impact in mitochondrial disease, with the overall aim of identifying novel therapeutic targets that will lead to effective treatments for mitochondrial disease. Furthermore, the high applicability of the tools generated will allow significant breakthroughs in the research of other pathologies with mitochondrial affectation such as diabetes or neurodegenerative processes.
Summary
Mitochondria generate most of the energy cells require to function. Deficits in the mitochondrial energy-generating machinery affect 1:5,000 children and cause progressive, debilitating, and usually fatal pathologies collectively known as primary mitochondrial disease. To date, there is no cure for mitochondrial disease and existing treatments are highly ineffective and mostly palliative. High-energy-requiring cells, such as neurons, are especially affected in mitochondrial disease. However, not all neuronal populations are equally affected. Furthermore, the molecular determinants of neuronal vulnerability to mitochondrial disease have not been adequately elucidated, representing a challenge for the development of efficient treatments for these pathologies. To improve on current knowledge on mitochondrial disease and to provide better therapeutic targets, this project focuses on developing ground-breaking mouse genetics and molecular biology tools that will allow the identification and dissection of the molecular determinants of neuronal vulnerability in mitochondrial disease with unprecedented definition. We will develop novel techniques to isolate both the mitochondrial and cytosolic translatome by using ribosomal tagging in vivo as well as to assess intact mitochondrial function with cell-type specificity and temporal resolution. These novel approaches will have a high impact in mitochondrial disease, with the overall aim of identifying novel therapeutic targets that will lead to effective treatments for mitochondrial disease. Furthermore, the high applicability of the tools generated will allow significant breakthroughs in the research of other pathologies with mitochondrial affectation such as diabetes or neurodegenerative processes.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym PRIORS
Project Neural circuit dynamics underlying expectation and their impact on the variability of perceptual choices
Researcher (PI) Jaime de la Rocha Vazquez
Host Institution (HI) CONSORCI INSTITUT D'INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Just as our experience has its origin in our perceptions, our perceptions are fundamentally shaped by our experience. How does the brain build expectations from experience and how do expectations impact perception? In a Bayesian framework, expectations determine the environment’s prior probability, which combined with stimulus information, can yield optimal decisions. While the accumulation-to-bound model describes temporal integration of sensory inputs and their combination with the prior, we still lack electrophysiological evidence showing neural circuits that integrate previous events adaptively to generate advantageous expectations.
I aim to understand (1) how circuits in the cerebral cortex integrate the recent history of stimuli and rewards to generate expectations, (2) how expectations are combined with sensory input across the processing hierarchy to bias decisions and (3) whether the dynamics of the expectation can dominate neuronal and choice variability. I will train rats in a new auditory discrimination task using predictable stimulus sequences that, once learned, are used to compute adaptive priors that improve discrimination. I will perform population recordings and optogenetic manipulations to identify the brain areas involved in the computation of priors in the task. To reveal the circuit mechanisms underlying the observed dynamics I will train a computational network model to classify fluctuating inputs and, by adapting its dynamics to the statistics of the stimulus sequence, accumulate evidence across trials to maximize performance. The model will generalize the accumulation-to-bound model by integrating information across various time scales and will partition choice variability into that caused by the dynamics of the prior or by fluctuations in the stimulus response. My proposal points at a paradigm shift from viewing neuronal variability as a corrupting source of noise to the result of our brain’s inevitable tendency to predict the future.
Summary
Just as our experience has its origin in our perceptions, our perceptions are fundamentally shaped by our experience. How does the brain build expectations from experience and how do expectations impact perception? In a Bayesian framework, expectations determine the environment’s prior probability, which combined with stimulus information, can yield optimal decisions. While the accumulation-to-bound model describes temporal integration of sensory inputs and their combination with the prior, we still lack electrophysiological evidence showing neural circuits that integrate previous events adaptively to generate advantageous expectations.
I aim to understand (1) how circuits in the cerebral cortex integrate the recent history of stimuli and rewards to generate expectations, (2) how expectations are combined with sensory input across the processing hierarchy to bias decisions and (3) whether the dynamics of the expectation can dominate neuronal and choice variability. I will train rats in a new auditory discrimination task using predictable stimulus sequences that, once learned, are used to compute adaptive priors that improve discrimination. I will perform population recordings and optogenetic manipulations to identify the brain areas involved in the computation of priors in the task. To reveal the circuit mechanisms underlying the observed dynamics I will train a computational network model to classify fluctuating inputs and, by adapting its dynamics to the statistics of the stimulus sequence, accumulate evidence across trials to maximize performance. The model will generalize the accumulation-to-bound model by integrating information across various time scales and will partition choice variability into that caused by the dynamics of the prior or by fluctuations in the stimulus response. My proposal points at a paradigm shift from viewing neuronal variability as a corrupting source of noise to the result of our brain’s inevitable tendency to predict the future.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym RECORTHA
Project Rewiring cortical areas through thalamocortical inputs
Researcher (PI) Guillermina Eloisa Lopez-Bendito
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Research into neuroplasticity has expanded rapidly over the past ten years and it has revealed the remarkable capacity of environmental inputs to shape both the juvenile and adult brain. Behavioural, electrophysiological and neuroimaging studies in deaf and blind humans have provided convincing evidence that alteration of cortical organization is correlated with enhanced capabilities of the spared modalities. What is the identity of the brain systems that are modified and what are the mechanisms that mediate such changes are major unresolved issues in our understanding of brain plasticity. RECORTHA aims to address this challenge and identify the mechanisms underlying the rewiring of brain connections with a particular focus on the thalamocortical system. We will adopt innovative multidisciplinary approaches (from gene to behaviour) to understand how thalamocortical wiring influences, maintains and ultimately shape the functional architecture of the cortex. Taking advantage of mouse genetics, we will generate new models of cross modal plasticity in which we can directly test the capacity of thalamocortical inputs to restore sensory information. Furthermore, we will determine to what extent this rewiring is triggered by activity dependent mechanisms in the thalamus. These findings will contribute to our understating of how reprogramming of cortical wiring takes place following brain damage that will be essential for efficient functional restoration in sensory disabilities.
Summary
Research into neuroplasticity has expanded rapidly over the past ten years and it has revealed the remarkable capacity of environmental inputs to shape both the juvenile and adult brain. Behavioural, electrophysiological and neuroimaging studies in deaf and blind humans have provided convincing evidence that alteration of cortical organization is correlated with enhanced capabilities of the spared modalities. What is the identity of the brain systems that are modified and what are the mechanisms that mediate such changes are major unresolved issues in our understanding of brain plasticity. RECORTHA aims to address this challenge and identify the mechanisms underlying the rewiring of brain connections with a particular focus on the thalamocortical system. We will adopt innovative multidisciplinary approaches (from gene to behaviour) to understand how thalamocortical wiring influences, maintains and ultimately shape the functional architecture of the cortex. Taking advantage of mouse genetics, we will generate new models of cross modal plasticity in which we can directly test the capacity of thalamocortical inputs to restore sensory information. Furthermore, we will determine to what extent this rewiring is triggered by activity dependent mechanisms in the thalamus. These findings will contribute to our understating of how reprogramming of cortical wiring takes place following brain damage that will be essential for efficient functional restoration in sensory disabilities.
Max ERC Funding
1 478 400 €
Duration
Start date: 2010-01-01, End date: 2015-06-30
Project acronym RememberEx
Project Human Subcortical-Cortical Circuit Dynamics for Remembering the Exceptional
Researcher (PI) Bryan STRANGE
Host Institution (HI) UNIVERSIDAD POLITECNICA DE MADRID
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary Our memory system is optimised for remembering the exceptional over the mundane. We remember better those events that violate predictions generated by the prevailing context, particularly because of surprise or emotional impact. Understanding how we form and retrieve long-term memories for important or salient events is critical for combating the rapidly growing incidence of pathologies associated with memory dysfunction with huge socio-econonomic burden. Human lesion and non-invasive functional imaging data, motivated by findings from animal models, have identified subcortical structures that are critical for upregulating hippocampal function during salient event memory. However, mechanistic understanding of these processes in humans remains scarce, and requires better experimental approaches such as direct intracranial recordings from, and focal electrical stimulation of, these subcortical structures.
This project will characterise human subcortico-cortical neuronal circuit dynamics associated with enhanced episodic memory for salient stimuli by studying direct recordings from human hippocampus, amygdala, nucleus accumbens, ventral midbrain and cortex. Within this framework, I will elucidate the electrophysiological mechanisms underlying amygdala-hippocampal-cortical coupling that lead to better memory for emotional stimuli, extend the hippocampal role in detecting unpredicted stimuli to define its role in orchestrating cortical dynamics in unpredictable contexts, and discover the neuronal response profile of the human mesolimbic dopamine system during salient stimulus encoding. The predicted results, based on my own preliminary data, will offer several conceptual breakthroughs, particularly regarding hippocampal function and the role of dopaminergic ventral midbrain in memory. The knowledge gained from this project is a fundamental requirement for designing therapeutic interventions for patients with memory deficits and other neuropsychiatric disorders.
Summary
Our memory system is optimised for remembering the exceptional over the mundane. We remember better those events that violate predictions generated by the prevailing context, particularly because of surprise or emotional impact. Understanding how we form and retrieve long-term memories for important or salient events is critical for combating the rapidly growing incidence of pathologies associated with memory dysfunction with huge socio-econonomic burden. Human lesion and non-invasive functional imaging data, motivated by findings from animal models, have identified subcortical structures that are critical for upregulating hippocampal function during salient event memory. However, mechanistic understanding of these processes in humans remains scarce, and requires better experimental approaches such as direct intracranial recordings from, and focal electrical stimulation of, these subcortical structures.
This project will characterise human subcortico-cortical neuronal circuit dynamics associated with enhanced episodic memory for salient stimuli by studying direct recordings from human hippocampus, amygdala, nucleus accumbens, ventral midbrain and cortex. Within this framework, I will elucidate the electrophysiological mechanisms underlying amygdala-hippocampal-cortical coupling that lead to better memory for emotional stimuli, extend the hippocampal role in detecting unpredicted stimuli to define its role in orchestrating cortical dynamics in unpredictable contexts, and discover the neuronal response profile of the human mesolimbic dopamine system during salient stimulus encoding. The predicted results, based on my own preliminary data, will offer several conceptual breakthroughs, particularly regarding hippocampal function and the role of dopaminergic ventral midbrain in memory. The knowledge gained from this project is a fundamental requirement for designing therapeutic interventions for patients with memory deficits and other neuropsychiatric disorders.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym SENSORTHALAMUS
Project Thalamic control of Neuroplasticity
Researcher (PI) Guillermina Eloisa Lopez bendito
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary The cerebral cortex is organized into highly specialized sensory areas. Thus, it is fundamental to understand how these areas acquire and maintain their identity and functional organization. Challenging normal brain development and forcing the brain to the limits of plasticity, offers us the possibility to shed light on these issues. Accordingly, we shall use prenatal sensory deprivation as a model to understand the mechanisms underlying early neuroplasticity, events that could influence the natural organization of sensory cortical areas. Early sensory deprivation produces profound changes in the cortex, provoking the reorganization of both the deprived and the spared cortical territories. Classically, this adaptation is thought to require sensory experience from the intact sensory modalities. However, our recent data from embryonic deprived mice challenge this view, suggesting that a component independent of experience contributes to this reorganization and that the thalamus plays a pivotal role in these events. Hence, we now propose to adopt multidisciplinary and innovative approaches to characterize the structural, genetic and functional rearrangements in the thalamus following embryonic sensory deprivation, and to define the factors and mechanisms that drive cortical specificity. Experimental results from sensory deprived animals in which the thalamus and gene expression is manipulated in vivo, will be integrated to explain when and how neuroplastic cortical adaptations are triggered in the deprived brain. To further understand the rewiring capacity of thalamic neurons and their potential role in sensory restoration, we will adopt a high-risk, high-gain approach to reprogramme nuclei specific thalamic neurons. The novel information obtained will establish how sensory inputs and thalamocortical connections govern cortical activity and architecture, ultimately sculpting perceptual behaviour.
Summary
The cerebral cortex is organized into highly specialized sensory areas. Thus, it is fundamental to understand how these areas acquire and maintain their identity and functional organization. Challenging normal brain development and forcing the brain to the limits of plasticity, offers us the possibility to shed light on these issues. Accordingly, we shall use prenatal sensory deprivation as a model to understand the mechanisms underlying early neuroplasticity, events that could influence the natural organization of sensory cortical areas. Early sensory deprivation produces profound changes in the cortex, provoking the reorganization of both the deprived and the spared cortical territories. Classically, this adaptation is thought to require sensory experience from the intact sensory modalities. However, our recent data from embryonic deprived mice challenge this view, suggesting that a component independent of experience contributes to this reorganization and that the thalamus plays a pivotal role in these events. Hence, we now propose to adopt multidisciplinary and innovative approaches to characterize the structural, genetic and functional rearrangements in the thalamus following embryonic sensory deprivation, and to define the factors and mechanisms that drive cortical specificity. Experimental results from sensory deprived animals in which the thalamus and gene expression is manipulated in vivo, will be integrated to explain when and how neuroplastic cortical adaptations are triggered in the deprived brain. To further understand the rewiring capacity of thalamic neurons and their potential role in sensory restoration, we will adopt a high-risk, high-gain approach to reprogramme nuclei specific thalamic neurons. The novel information obtained will establish how sensory inputs and thalamocortical connections govern cortical activity and architecture, ultimately sculpting perceptual behaviour.
Max ERC Funding
1 966 771 €
Duration
Start date: 2015-07-01, End date: 2021-02-28
Project acronym SEROTONINANDDISEASE
Project Dissecting the gene regulatory mechanisms that generate serotonergic neurons and their link to mental disorders
Researcher (PI) Nuria Flames Bonilla
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS5, ERC-2011-StG_20101109
Summary Mental disorders constitute a human an economic burden for developed countries. Many mental disorders are linked to serotonin dysfunction, but the exact mechanism underlying these disorders is not well understood. Serotonin Related Mental Disorders (SRMD) are multigenic, making the identification of these mechanisms a difficult task. Understanding the molecular mechanisms that generate serotonergic neurons will provide us with the tools to identify mutations that could predispose to SRMD. In this grant we will use a multidisciplinary approach to dissect the transcriptional mechanisms that generate serotonergic neurons and use this knowledge to identify genetic links to SRMD. Serotonergic neurons are very ancient in evolution and enzymes and transporters responsible for the production of serotonin (serotonin pathway genes) are very well conserved in all metazoans. We would take advantage of this evolutionary conservation and use the genetic amenability of C. elegans to dissect the genetic mechanisms responsible for the generation of the serotonergic neurons. We will apply the lessons learned from C. elegans to unravel analogous mechanisms regulating mouse serotonergic differentiation. Our preliminary results show that the serotonergic pathway genes are co-regulated by the same factors and that this mechanism is evolutionary conserved. We will identify the cis-acting sequences (serotonergic motif) and trans-acting factors responsible for the activation of the serotonergic features, both in worms and mice. Finally, we will apply our knowledge on serotonergic differentiation to identify genetic association to SRMDs. Mutations in the serotonergic motif could lead to defects on the expression of the serotonergic genes, resulting in a dysfunctional serotonergic neuron. We will build a database of all human serotonergic motifs and look for mutations in these sites in SRMD patients. In summary, this grant will give us the tools to better understand and treat SRMD.
Summary
Mental disorders constitute a human an economic burden for developed countries. Many mental disorders are linked to serotonin dysfunction, but the exact mechanism underlying these disorders is not well understood. Serotonin Related Mental Disorders (SRMD) are multigenic, making the identification of these mechanisms a difficult task. Understanding the molecular mechanisms that generate serotonergic neurons will provide us with the tools to identify mutations that could predispose to SRMD. In this grant we will use a multidisciplinary approach to dissect the transcriptional mechanisms that generate serotonergic neurons and use this knowledge to identify genetic links to SRMD. Serotonergic neurons are very ancient in evolution and enzymes and transporters responsible for the production of serotonin (serotonin pathway genes) are very well conserved in all metazoans. We would take advantage of this evolutionary conservation and use the genetic amenability of C. elegans to dissect the genetic mechanisms responsible for the generation of the serotonergic neurons. We will apply the lessons learned from C. elegans to unravel analogous mechanisms regulating mouse serotonergic differentiation. Our preliminary results show that the serotonergic pathway genes are co-regulated by the same factors and that this mechanism is evolutionary conserved. We will identify the cis-acting sequences (serotonergic motif) and trans-acting factors responsible for the activation of the serotonergic features, both in worms and mice. Finally, we will apply our knowledge on serotonergic differentiation to identify genetic association to SRMDs. Mutations in the serotonergic motif could lead to defects on the expression of the serotonergic genes, resulting in a dysfunctional serotonergic neuron. We will build a database of all human serotonergic motifs and look for mutations in these sites in SRMD patients. In summary, this grant will give us the tools to better understand and treat SRMD.
Max ERC Funding
1 931 621 €
Duration
Start date: 2012-12-01, End date: 2018-11-30
