Project acronym AXONENDO
Project Endosomal control of local protein synthesis in axons
Researcher (PI) Jean-Michel Cioni
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.
Summary
Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.
Max ERC Funding
1 499 563 €
Duration
Start date: 2020-09-01, End date: 2025-08-31
Project acronym COGSYSTEMS
Project Understanding actions and intentions of others
Researcher (PI) Giacomo Rizzolatti
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PARMA
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.
Summary
How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.
Max ERC Funding
1 992 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym CONCEPT
Project Construction of Perception from Touch Signals
Researcher (PI) Mathew Diamond
Host Institution (HI) SCUOLA INTERNAZIONALE SUPERIORE DI STUDI AVANZATI DI TRIESTE
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Our sensory systems gather stimuli as elemental physical features yet we perceive a world made up of familiar objects, not wavelengths or vibrations. Perception occurs when the neuronal representation of physical parameters is transformed into the neuronal representation of meaningful objects. How does this recoding occur? An ideal platform for the inquiry is the rat whisker sensory system: it produces fast and accurate judgments of complex stimuli, yet can be broken down into accessible neuronal mechanisms. CONCEPT will examine the process that begins with whisker motion and ends with perception of the contacted object. Understanding the general principles for the construction of perception will help explain why we experience the world as we do.
The main hypothesis is that graded neuronal representations at early processing stages are “fractured” to generate discrete object representations at late processing stages. Of particular interest is the emergence of object representations as the meaning of new stimuli is acquired.
We will collect multi-site single-unit and local field potential signals simultaneously with precise behavioral indices, and will interpret data through advanced computational methods. We will begin by quantifying whisker motion as rats discriminate texture, thus defining the raw material on which the brain operates. Next, we will characterize the transformation of texture along an intracortical stream from sensory areas (where we expect that neurons encode whisker kinematics) to frontal and rhinal areas (where we expect that neurons encode objects extracted from the graded physical continuum) and hippocampus (where we expect that neurons encode objects in conjunction with context). We will test candidate processing schemes by manipulating perception on single trials using optogenetic methods.
Summary
Our sensory systems gather stimuli as elemental physical features yet we perceive a world made up of familiar objects, not wavelengths or vibrations. Perception occurs when the neuronal representation of physical parameters is transformed into the neuronal representation of meaningful objects. How does this recoding occur? An ideal platform for the inquiry is the rat whisker sensory system: it produces fast and accurate judgments of complex stimuli, yet can be broken down into accessible neuronal mechanisms. CONCEPT will examine the process that begins with whisker motion and ends with perception of the contacted object. Understanding the general principles for the construction of perception will help explain why we experience the world as we do.
The main hypothesis is that graded neuronal representations at early processing stages are “fractured” to generate discrete object representations at late processing stages. Of particular interest is the emergence of object representations as the meaning of new stimuli is acquired.
We will collect multi-site single-unit and local field potential signals simultaneously with precise behavioral indices, and will interpret data through advanced computational methods. We will begin by quantifying whisker motion as rats discriminate texture, thus defining the raw material on which the brain operates. Next, we will characterize the transformation of texture along an intracortical stream from sensory areas (where we expect that neurons encode whisker kinematics) to frontal and rhinal areas (where we expect that neurons encode objects extracted from the graded physical continuum) and hippocampus (where we expect that neurons encode objects in conjunction with context). We will test candidate processing schemes by manipulating perception on single trials using optogenetic methods.
Max ERC Funding
2 500 000 €
Duration
Start date: 2012-06-01, End date: 2018-05-31
Project acronym DisConn
Project Neural drivers of functional disconnectivity in brain disorders
Researcher (PI) Alessandro GOZZI
Host Institution (HI) FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Summary
A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling?
This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse.
By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.
Max ERC Funding
1 498 125 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym GenEdiDS
Project Rescuing Cognitive Deficits in Neurodevelopmental Disorders by Gene Editing in Brain Development: the Case of Down Syndrome
Researcher (PI) Laura Cancedda
Host Institution (HI) FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Neurodevelopmental disorders (ND) are chronic psychiatric conditions with different etiologies, but most share a strong genetic component, defective brain development, and cognitive impairment. Currently, treatment options are very limited, and early educational intervention is the cornerstone for the management of cognitive impairment in most ND, indicating the positive effect of early actions during brain development. Among ND, Down syndrome (DS) is caused by the presence of an extra chromosome 21, and it represents the leading cause of genetically-defined intellectual disability. Different pharmacological treatments targeting one of the many pathways downstream of the triplicated genes have been shown to rescue cognitive impairment in DS animal models. Nevertheless, most of these preclinical studies have been performed postnatally and often in adults, possibly because of concerns of unwanted drug side effects that may have long-lasting noxious sequelae on a developing brain at embryonic stages. On the other hand, viral (but also non-viral) gene therapy approaches in animal models of ND have been mostly neglected because of technical and ethical issues, when considered in the light of future translational applications. Yet, DS is mostly diagnosed prenatally, when many of its brain developmental abnormalities originate. Here, we will investigate whether in utero manipulation of specific and possibly converging gene networks in neuronal progenitors of DS mice by CRISPR-Cas9 gene-editing technology, may recover brain development and cognitive deficits later in life. Specifically targeting neuronal progenitors will allow us to act at early stages of brain development, while avoiding the involvement of genetic editing of germline cells and all related ethical issues. In parallel, we will also develop safer (viral-free) technological approaches for genetic manipulations in utero to minimize technical issues in the view of potential future translational applications.
Summary
Neurodevelopmental disorders (ND) are chronic psychiatric conditions with different etiologies, but most share a strong genetic component, defective brain development, and cognitive impairment. Currently, treatment options are very limited, and early educational intervention is the cornerstone for the management of cognitive impairment in most ND, indicating the positive effect of early actions during brain development. Among ND, Down syndrome (DS) is caused by the presence of an extra chromosome 21, and it represents the leading cause of genetically-defined intellectual disability. Different pharmacological treatments targeting one of the many pathways downstream of the triplicated genes have been shown to rescue cognitive impairment in DS animal models. Nevertheless, most of these preclinical studies have been performed postnatally and often in adults, possibly because of concerns of unwanted drug side effects that may have long-lasting noxious sequelae on a developing brain at embryonic stages. On the other hand, viral (but also non-viral) gene therapy approaches in animal models of ND have been mostly neglected because of technical and ethical issues, when considered in the light of future translational applications. Yet, DS is mostly diagnosed prenatally, when many of its brain developmental abnormalities originate. Here, we will investigate whether in utero manipulation of specific and possibly converging gene networks in neuronal progenitors of DS mice by CRISPR-Cas9 gene-editing technology, may recover brain development and cognitive deficits later in life. Specifically targeting neuronal progenitors will allow us to act at early stages of brain development, while avoiding the involvement of genetic editing of germline cells and all related ethical issues. In parallel, we will also develop safer (viral-free) technological approaches for genetic manipulations in utero to minimize technical issues in the view of potential future translational applications.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym HD-DittoGraph
Project HD-DittoGraph: a digital human Embryonic Stem Cell platform for Huntington's repeats
Researcher (PI) Elena CATTANEO
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary This proposal is aimed at identifying the molecular mechanisms that have brought the human Huntington Disease-causing Huntingtin (Htt) exon 1, with its pure and unstable CAG repeat, to be shaped the way it is today. Specifically, we intend to screen for genetic elements affecting Htt repeat length instability in dividing and postmitotic neuronal cells. The novelty of our approach relies on the construction of a human embryonic stem (hES) cell platform that couples highly efficient CRISPR/Cas9 technology with genome-wide screenings and third generation sequencing, to test the contribution of thousands of unequivocally barcoded cis and trans modifiers on Htt exon 1 repeats instability.
In Aim 1, we will test the contribution of cis-modifiers to repeat instability during multiple mitotic divisions, by generating a hES cell platform where we will subsequently introduce a barcoded donor library of different Htt exon 1 constructs, with different CAG and flanking sequences, at the Htt locus.
In Aim 2 our hES cell platform will be implemented with inducible Cas9 elements and sgRNAs libraries to perform genome-wide loss and gain of function (LOF, GOF) screenings of trans-acting modifiers of repeat sequence and size. The sgRNAs will act as barcodes for the modifier genes, allowing to test their causative role on repeat size changes.
In Aim 3, we will exploit the neurogenic potential of hES cells in our LOF and GOF platforms to identify Htt exon 1 repeat modifiers in differentiating striatal neurons. Candidate modifier genes will be individually validated and tested for their functional impact on gene networks by transcriptome analysis.
In all approaches, third generation sequencing and ad hoc computational pipelines will allow the simultaneous identification of the repeat changes and their association to the corresponding modifiers. Overall, this research proposal is expected to provide key molecular and genetic insights into the process of Htt repeat expansion in human
Summary
This proposal is aimed at identifying the molecular mechanisms that have brought the human Huntington Disease-causing Huntingtin (Htt) exon 1, with its pure and unstable CAG repeat, to be shaped the way it is today. Specifically, we intend to screen for genetic elements affecting Htt repeat length instability in dividing and postmitotic neuronal cells. The novelty of our approach relies on the construction of a human embryonic stem (hES) cell platform that couples highly efficient CRISPR/Cas9 technology with genome-wide screenings and third generation sequencing, to test the contribution of thousands of unequivocally barcoded cis and trans modifiers on Htt exon 1 repeats instability.
In Aim 1, we will test the contribution of cis-modifiers to repeat instability during multiple mitotic divisions, by generating a hES cell platform where we will subsequently introduce a barcoded donor library of different Htt exon 1 constructs, with different CAG and flanking sequences, at the Htt locus.
In Aim 2 our hES cell platform will be implemented with inducible Cas9 elements and sgRNAs libraries to perform genome-wide loss and gain of function (LOF, GOF) screenings of trans-acting modifiers of repeat sequence and size. The sgRNAs will act as barcodes for the modifier genes, allowing to test their causative role on repeat size changes.
In Aim 3, we will exploit the neurogenic potential of hES cells in our LOF and GOF platforms to identify Htt exon 1 repeat modifiers in differentiating striatal neurons. Candidate modifier genes will be individually validated and tested for their functional impact on gene networks by transcriptome analysis.
In all approaches, third generation sequencing and ad hoc computational pipelines will allow the simultaneous identification of the repeat changes and their association to the corresponding modifiers. Overall, this research proposal is expected to provide key molecular and genetic insights into the process of Htt repeat expansion in human
Max ERC Funding
2 040 943 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym HUMO
Project What is everybody doing? Social prediction, categorization, and monitoring in the Prefrontal Cortex of the Macaque adopting a new human-monkey (H-M) interactive paradigm.
Researcher (PI) Aldo Genovesio
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Summary
Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Max ERC Funding
1 028 750 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym LEARN2SEE
Project Invariant visual object representations in the early postnatal and adult cortex: bridging theory, model and neurobiology
Researcher (PI) Davide Franco Zoccolan
Host Institution (HI) SCUOLA INTERNAZIONALE SUPERIORE DI STUDI AVANZATI DI TRIESTE
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary Our visual system can effortlessly recognize hundreds of thousands of objects in spite of tremendous variation in their appearance, resulting, for instance, from changes in object position and pose. Achieving such an invariant representation of the visual world is an extremely challenging computational problem that even the most advanced artificial vision systems are not fully able to solve. This is why understanding the neuronal mechanisms underlying object vision is one of the major challenges of systems neuroscience and a crucial step towards developing artificial vision systems and visual prostheses.
Little is known yet about how the brain develops and maintains invariant object representations. The leading theory is that visual neurons exploit the spatiotemporal continuity of visual experience (i.e., the natural tendency of different object views to occur nearby in time) to learn to produce similar responses for temporally contiguous stimuli, so as to factorize object identity from other variables (such as position, size, etc.). This Unsupervised Temporal Learning (UTL) strategy has been instantiated in a number of computational frameworks, but its empirical investigation has received little attention. My proposal will use the visual system of the rat to address key questions about the nature of UTL and other learning theories, such as their impact on recognition behavior and object representations at both single-neuron and population level, and their role during early postnatal development. This will be achieved through a highly multidisciplinary approach, including high-throughput behavioral testing, in vivo neuronal recordings, immediate-early gene labeling, controlled-rearing in virtual visual environments, and computational modeling. This will lead to ground-breaking insights into the learning principles that sculpt the cortical representations of visual objects through unsupervised exposure to the spatiotemporal statistics of visual experience.
Summary
Our visual system can effortlessly recognize hundreds of thousands of objects in spite of tremendous variation in their appearance, resulting, for instance, from changes in object position and pose. Achieving such an invariant representation of the visual world is an extremely challenging computational problem that even the most advanced artificial vision systems are not fully able to solve. This is why understanding the neuronal mechanisms underlying object vision is one of the major challenges of systems neuroscience and a crucial step towards developing artificial vision systems and visual prostheses.
Little is known yet about how the brain develops and maintains invariant object representations. The leading theory is that visual neurons exploit the spatiotemporal continuity of visual experience (i.e., the natural tendency of different object views to occur nearby in time) to learn to produce similar responses for temporally contiguous stimuli, so as to factorize object identity from other variables (such as position, size, etc.). This Unsupervised Temporal Learning (UTL) strategy has been instantiated in a number of computational frameworks, but its empirical investigation has received little attention. My proposal will use the visual system of the rat to address key questions about the nature of UTL and other learning theories, such as their impact on recognition behavior and object representations at both single-neuron and population level, and their role during early postnatal development. This will be achieved through a highly multidisciplinary approach, including high-throughput behavioral testing, in vivo neuronal recordings, immediate-early gene labeling, controlled-rearing in virtual visual environments, and computational modeling. This will lead to ground-breaking insights into the learning principles that sculpt the cortical representations of visual objects through unsupervised exposure to the spatiotemporal statistics of visual experience.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym MINDTRAVEL
Project Travels of the Mind: Modes of brain functioning in complex dynamic environments
Researcher (PI) Emiliano Macaluso
Host Institution (HI) FONDAZIONE SANTA LUCIA
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Subjective everyday experience entails a well-structured and continuous flow of sensory signals, actions, thoughts and emotions. How does the brain build such a coherent representation of space and time despite the vast amount and confusing nature of the input? Furthermore, what are the physiological constraints preventing simultaneous awareness of multiple spatial and temporal instances? Here I propose a novel approach ("brain modes") to investigate these issues within life-like experimental settings. I will investigate how the brain selects and integrates relevant information using complex dynamic environments that includes space, time and multisensorial inputs. Combining model-free and model-driven analyses of functional imaging data I will examine: 1. How signals in different sensory modalities and same/different locations interact in complex environments; 2. How contextual information influences memory encoding and retrieval and the ability to integrate current sensory signals with events in the past. 3. How prospective goals and expectancies arising from the temporal dynamic of the context influence on-line processing. My expectation is that the results will reveal novel mechanisms underlying the ability to organise information in an orderly manner, on a time-line spanning the past, the present and the future; and how we can direct our thoughts along this time-line. My investigation will provide new evidence on the capacity limitations of this selection process and how integration and competition interact to form a representation of the external world that evolves as a coherent flow through space and time. Potential practical implications are foreseen for the design of brain-machine interfaces and for understanding the abnormal perceptions of mental illness.
Summary
Subjective everyday experience entails a well-structured and continuous flow of sensory signals, actions, thoughts and emotions. How does the brain build such a coherent representation of space and time despite the vast amount and confusing nature of the input? Furthermore, what are the physiological constraints preventing simultaneous awareness of multiple spatial and temporal instances? Here I propose a novel approach ("brain modes") to investigate these issues within life-like experimental settings. I will investigate how the brain selects and integrates relevant information using complex dynamic environments that includes space, time and multisensorial inputs. Combining model-free and model-driven analyses of functional imaging data I will examine: 1. How signals in different sensory modalities and same/different locations interact in complex environments; 2. How contextual information influences memory encoding and retrieval and the ability to integrate current sensory signals with events in the past. 3. How prospective goals and expectancies arising from the temporal dynamic of the context influence on-line processing. My expectation is that the results will reveal novel mechanisms underlying the ability to organise information in an orderly manner, on a time-line spanning the past, the present and the future; and how we can direct our thoughts along this time-line. My investigation will provide new evidence on the capacity limitations of this selection process and how integration and competition interact to form a representation of the external world that evolves as a coherent flow through space and time. Potential practical implications are foreseen for the design of brain-machine interfaces and for understanding the abnormal perceptions of mental illness.
Max ERC Funding
1 219 597 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym NEVAI
Project Neurovascular Interactions and Pathfinding in the Spinal Motor System
Researcher (PI) Dario Bonanomi
Host Institution (HI) OSPEDALE SAN RAFFAELE SRL
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary "Neurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities.
My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multi-disciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets and novel mouse mutants for future studies of neurovascular communication and patterning."
Summary
"Neurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities.
My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multi-disciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets and novel mouse mutants for future studies of neurovascular communication and patterning."
Max ERC Funding
1 653 000 €
Duration
Start date: 2015-01-01, End date: 2019-12-31
