Neurobiology (Donato)Head of Research Unit Prof. Dr.Flavio DonatoOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 4 foundShow per page10 10 20 50 How do you build a cognitive map? Dissecting the mechanisms driving the development of the brain's representation of space in the entorhinal-hippocampal network Research Project | 6 Project MembersPuzzled by the observation that rats could find shortcuts when navigating a maze, in 1948 Edward Tolman proposed that animals are able to create an internal representation of the environments they move in, and use this representation to implement sophisticated goal-directed behaviors, like finding shortcuts. He called this representation a "cognitive map" and speculated that such a map could be efficiently used for other psychological functions, such as decision making, learning, memory, reasoning, and imagination.In the 70 years that followed, neural correlates of the cognitive map were found in the entorhinal cortex and hippocampus of the mammalian brain, instantiated in single neurons whose activity is tuned to specific variables associated with space, like the animal's location (place and grid cells), orientation (head-direction cells), or proximity to boundaries (border cells).The cognitive map is not hard-wired into an animal's brain: infant animals are equipped with only a rudimentary representation of space, whose structural and functional correlates develop over an extended period of time after birth. During this time, spatially-tuned activity patterns like those of place and grid cells emerge and increase their stability and precision, while the animal progressively deploys more sophisticated navigational strategies to reach its goals. The mechanisms by which a developing brain acquires the ability to create an internal representation of space remain to be elucidated. How do you build a cognitive map during development? To answer this question, I propose to use a systems-neuroscience approach to study the development of the entorhinal-hippocampal network, in order to dissect the contribution of specific subpopulations of neurons to the assembly and function of the cognitive map.In my previous work, I discovered that an activity-dependent signal relayed by entorhinal stellate cells drives the step-wise maturation of the entorhinal-hippocampal network. Moreover, I revealed that entorhinal activity is temporally organized in stereotyped motifs like ensembles and sequences as would be expected in an "attractor network", which might support the firing of grid and place cells. Here, I will build on this knowledge to answer three main questions: (1) What is the origin of the signals that drive the maturation of the entorhinal-hippocampal network? (2) Why is entorhinal activity temporally organized into stereotyped motifs like ensembles and sequences, and when and how do these motifs emerge during development? (3) What is the impact of early-life experience on the function of the cognitive map? My hypothesis are that (1) the instructive signals for the maturation of the entorhinal-hippocampal network originate cell-autonomously in stellate cells, and their propagation is modulated by the animal´s locomotion early during development; (2) the interplay between stellate cells and the hippocampus drives the progressive emergence of an attractor network in the medial entorhinal cortex, for the production of temporally organized activity motifs; (3) the integration of sensory and motor experience early during development drives the emergence and refinement of the cognitive map.To test these hypotheses, we will deploy cutting-edge technologies to study the structure and function of developing neuronal circuits. We will implement a viral strategy to visualize neurons with monosynaptic connections to stellate cells, and optogenetic and chemogenetic approaches to test the involvement of these neurons in the maturation of the entorhinal-hippocampal network. We will make use of 2-photon calcium imaging to simultaneously record the activity of hundreds of entorhinal neurons over consecutive developmental stages in behaving pups, and use dimensionality-reduction techniques to visualize stereotyped activity motifs in their population activity. We will use chronically-implanted electrodes to identify spatially-tuned activity patterns in the entorhinal cortex and hippocampus, and characterize their properties when animals are raised in sensory-poor conditions.The knowledge gathered with my projects will represent a breakthrough in our understanding of the development and function of the cognitive map, and it will provide unprecedented insight into the mechanisms driving the functional maturation of circuits located in high-end areas of cortex, where cognitive functions arise. But this proposal has the potential to go beyond basic research. Since psychological traumas and genetic dysfunctions targeting the development of higher-cognitive areas have been implicated in disorders like autism, depression, or intellectual disabilities, the experiments of this proposal will lay the foundation for a larger research vision aimed at identifying and correcting pathological deviations that have their origin in neurodevelopmental disorders. RigidPlasticNeurons Research Project | 2 Project MembersNo Description available Hippocampal circuits for the encoding of early-life memories. Research Project | 5 Project MembersThe infant brain is a formidable learning machine. But is it able to encode memories of early-life experiences? Since most of us don't remember what happened during the first years of our lives, for a long time this question has been open to debate. Recent evidence suggests that, even if we cannot recall them, early-life memories are encoded in the developing hippocampus, persist in a silent state into adulthood, and can affect the acquisition of new information later in life. We know very little about how the infant brain encodes early-life memories, despite the fact that our earliest experiences can stick with us and influence our behaviour as adults. How can the infant hippocampus produce long-lasting memory traces when its circuits are not yet mature? Why can't we remember early-life memories? And how can infant memories have long-lasting effects if we can't recall them? To answer these questions, in the following project we propose to study memory processes in the developing brain using the mouse as a model organism. We will implement a combination of genetics, viral tagging, calcium imaging, and opto- and chemogenetic methodologies, in association with behavioural paradigms, to track in vivo the activity of a large number of neurons as the brain matures, and to gain fundamental insights into the early functions of the mammalian memory system. The aims of this project are: to understand how the infant hippocampus produces neuronal ensembles to represent early-life experiences; to identify and dissect the neural circuits encoding infant memories; and to unravel how neurons supporting silent memories created during infancy influence learning processes in adults. By bridging developmental, systems, and behavioural neuroscience, our ambition is to understand how the developing brain encodes memories of early-life experiences, and how infant memories influence the operations of higher-order cognitive functions later in life. Grid cells and the functional correlates of space in the adult brain Research Project | 4 Project MembersThe medial entorhinal cortex (MEC) supports the brain's representation of space with distinct cell types whose firing is tuned to features of the environment (grid, border, and object-vector cells) or navigation (head-direction and speed cells), and whose somata are anatomically intermingled in layer 2 of the MEC (MEC-L2). Since no single sensory stimulus can faithfully predict the firing of these cells, and activity patterns are preserved across environments and brain states, attractor network models postulate that spatially-tuned firing emerges from specific connectivity motives among neurons of the MEC. To dissect the topology of such motives, we will study how activity self-organizes in conditions in which the path integrator of MEC-L2 is able to spontaneously drift along with the connectivity matrix of the network. To this end, we will use 2-photon calcium imaging to monitor the activity of large populations of MEC-L2 neurons in head-fixed mice running on a wheel in darkness, in the absence of external sensory feedback tuned to navigation. To reveal network dynamics under these conditions, we will apply both linear and non-linear dimensionality reduction techniques to the spike matrix of each individual session. Our aim is to dissect the rules governing connectivity in the entorhinal cortex and understand how the MEC-L2 network supports the production of regular and abstract firing patterns like those of grid cells. 1 1 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 4 foundShow per page10 10 20 50 How do you build a cognitive map? Dissecting the mechanisms driving the development of the brain's representation of space in the entorhinal-hippocampal network Research Project | 6 Project MembersPuzzled by the observation that rats could find shortcuts when navigating a maze, in 1948 Edward Tolman proposed that animals are able to create an internal representation of the environments they move in, and use this representation to implement sophisticated goal-directed behaviors, like finding shortcuts. He called this representation a "cognitive map" and speculated that such a map could be efficiently used for other psychological functions, such as decision making, learning, memory, reasoning, and imagination.In the 70 years that followed, neural correlates of the cognitive map were found in the entorhinal cortex and hippocampus of the mammalian brain, instantiated in single neurons whose activity is tuned to specific variables associated with space, like the animal's location (place and grid cells), orientation (head-direction cells), or proximity to boundaries (border cells).The cognitive map is not hard-wired into an animal's brain: infant animals are equipped with only a rudimentary representation of space, whose structural and functional correlates develop over an extended period of time after birth. During this time, spatially-tuned activity patterns like those of place and grid cells emerge and increase their stability and precision, while the animal progressively deploys more sophisticated navigational strategies to reach its goals. The mechanisms by which a developing brain acquires the ability to create an internal representation of space remain to be elucidated. How do you build a cognitive map during development? To answer this question, I propose to use a systems-neuroscience approach to study the development of the entorhinal-hippocampal network, in order to dissect the contribution of specific subpopulations of neurons to the assembly and function of the cognitive map.In my previous work, I discovered that an activity-dependent signal relayed by entorhinal stellate cells drives the step-wise maturation of the entorhinal-hippocampal network. Moreover, I revealed that entorhinal activity is temporally organized in stereotyped motifs like ensembles and sequences as would be expected in an "attractor network", which might support the firing of grid and place cells. Here, I will build on this knowledge to answer three main questions: (1) What is the origin of the signals that drive the maturation of the entorhinal-hippocampal network? (2) Why is entorhinal activity temporally organized into stereotyped motifs like ensembles and sequences, and when and how do these motifs emerge during development? (3) What is the impact of early-life experience on the function of the cognitive map? My hypothesis are that (1) the instructive signals for the maturation of the entorhinal-hippocampal network originate cell-autonomously in stellate cells, and their propagation is modulated by the animal´s locomotion early during development; (2) the interplay between stellate cells and the hippocampus drives the progressive emergence of an attractor network in the medial entorhinal cortex, for the production of temporally organized activity motifs; (3) the integration of sensory and motor experience early during development drives the emergence and refinement of the cognitive map.To test these hypotheses, we will deploy cutting-edge technologies to study the structure and function of developing neuronal circuits. We will implement a viral strategy to visualize neurons with monosynaptic connections to stellate cells, and optogenetic and chemogenetic approaches to test the involvement of these neurons in the maturation of the entorhinal-hippocampal network. We will make use of 2-photon calcium imaging to simultaneously record the activity of hundreds of entorhinal neurons over consecutive developmental stages in behaving pups, and use dimensionality-reduction techniques to visualize stereotyped activity motifs in their population activity. We will use chronically-implanted electrodes to identify spatially-tuned activity patterns in the entorhinal cortex and hippocampus, and characterize their properties when animals are raised in sensory-poor conditions.The knowledge gathered with my projects will represent a breakthrough in our understanding of the development and function of the cognitive map, and it will provide unprecedented insight into the mechanisms driving the functional maturation of circuits located in high-end areas of cortex, where cognitive functions arise. But this proposal has the potential to go beyond basic research. Since psychological traumas and genetic dysfunctions targeting the development of higher-cognitive areas have been implicated in disorders like autism, depression, or intellectual disabilities, the experiments of this proposal will lay the foundation for a larger research vision aimed at identifying and correcting pathological deviations that have their origin in neurodevelopmental disorders. RigidPlasticNeurons Research Project | 2 Project MembersNo Description available Hippocampal circuits for the encoding of early-life memories. Research Project | 5 Project MembersThe infant brain is a formidable learning machine. But is it able to encode memories of early-life experiences? Since most of us don't remember what happened during the first years of our lives, for a long time this question has been open to debate. Recent evidence suggests that, even if we cannot recall them, early-life memories are encoded in the developing hippocampus, persist in a silent state into adulthood, and can affect the acquisition of new information later in life. We know very little about how the infant brain encodes early-life memories, despite the fact that our earliest experiences can stick with us and influence our behaviour as adults. How can the infant hippocampus produce long-lasting memory traces when its circuits are not yet mature? Why can't we remember early-life memories? And how can infant memories have long-lasting effects if we can't recall them? To answer these questions, in the following project we propose to study memory processes in the developing brain using the mouse as a model organism. We will implement a combination of genetics, viral tagging, calcium imaging, and opto- and chemogenetic methodologies, in association with behavioural paradigms, to track in vivo the activity of a large number of neurons as the brain matures, and to gain fundamental insights into the early functions of the mammalian memory system. The aims of this project are: to understand how the infant hippocampus produces neuronal ensembles to represent early-life experiences; to identify and dissect the neural circuits encoding infant memories; and to unravel how neurons supporting silent memories created during infancy influence learning processes in adults. By bridging developmental, systems, and behavioural neuroscience, our ambition is to understand how the developing brain encodes memories of early-life experiences, and how infant memories influence the operations of higher-order cognitive functions later in life. Grid cells and the functional correlates of space in the adult brain Research Project | 4 Project MembersThe medial entorhinal cortex (MEC) supports the brain's representation of space with distinct cell types whose firing is tuned to features of the environment (grid, border, and object-vector cells) or navigation (head-direction and speed cells), and whose somata are anatomically intermingled in layer 2 of the MEC (MEC-L2). Since no single sensory stimulus can faithfully predict the firing of these cells, and activity patterns are preserved across environments and brain states, attractor network models postulate that spatially-tuned firing emerges from specific connectivity motives among neurons of the MEC. To dissect the topology of such motives, we will study how activity self-organizes in conditions in which the path integrator of MEC-L2 is able to spontaneously drift along with the connectivity matrix of the network. To this end, we will use 2-photon calcium imaging to monitor the activity of large populations of MEC-L2 neurons in head-fixed mice running on a wheel in darkness, in the absence of external sensory feedback tuned to navigation. To reveal network dynamics under these conditions, we will apply both linear and non-linear dimensionality reduction techniques to the spike matrix of each individual session. Our aim is to dissect the rules governing connectivity in the entorhinal cortex and understand how the MEC-L2 network supports the production of regular and abstract firing patterns like those of grid cells. 1 1
How do you build a cognitive map? Dissecting the mechanisms driving the development of the brain's representation of space in the entorhinal-hippocampal network Research Project | 6 Project MembersPuzzled by the observation that rats could find shortcuts when navigating a maze, in 1948 Edward Tolman proposed that animals are able to create an internal representation of the environments they move in, and use this representation to implement sophisticated goal-directed behaviors, like finding shortcuts. He called this representation a "cognitive map" and speculated that such a map could be efficiently used for other psychological functions, such as decision making, learning, memory, reasoning, and imagination.In the 70 years that followed, neural correlates of the cognitive map were found in the entorhinal cortex and hippocampus of the mammalian brain, instantiated in single neurons whose activity is tuned to specific variables associated with space, like the animal's location (place and grid cells), orientation (head-direction cells), or proximity to boundaries (border cells).The cognitive map is not hard-wired into an animal's brain: infant animals are equipped with only a rudimentary representation of space, whose structural and functional correlates develop over an extended period of time after birth. During this time, spatially-tuned activity patterns like those of place and grid cells emerge and increase their stability and precision, while the animal progressively deploys more sophisticated navigational strategies to reach its goals. The mechanisms by which a developing brain acquires the ability to create an internal representation of space remain to be elucidated. How do you build a cognitive map during development? To answer this question, I propose to use a systems-neuroscience approach to study the development of the entorhinal-hippocampal network, in order to dissect the contribution of specific subpopulations of neurons to the assembly and function of the cognitive map.In my previous work, I discovered that an activity-dependent signal relayed by entorhinal stellate cells drives the step-wise maturation of the entorhinal-hippocampal network. Moreover, I revealed that entorhinal activity is temporally organized in stereotyped motifs like ensembles and sequences as would be expected in an "attractor network", which might support the firing of grid and place cells. Here, I will build on this knowledge to answer three main questions: (1) What is the origin of the signals that drive the maturation of the entorhinal-hippocampal network? (2) Why is entorhinal activity temporally organized into stereotyped motifs like ensembles and sequences, and when and how do these motifs emerge during development? (3) What is the impact of early-life experience on the function of the cognitive map? My hypothesis are that (1) the instructive signals for the maturation of the entorhinal-hippocampal network originate cell-autonomously in stellate cells, and their propagation is modulated by the animal´s locomotion early during development; (2) the interplay between stellate cells and the hippocampus drives the progressive emergence of an attractor network in the medial entorhinal cortex, for the production of temporally organized activity motifs; (3) the integration of sensory and motor experience early during development drives the emergence and refinement of the cognitive map.To test these hypotheses, we will deploy cutting-edge technologies to study the structure and function of developing neuronal circuits. We will implement a viral strategy to visualize neurons with monosynaptic connections to stellate cells, and optogenetic and chemogenetic approaches to test the involvement of these neurons in the maturation of the entorhinal-hippocampal network. We will make use of 2-photon calcium imaging to simultaneously record the activity of hundreds of entorhinal neurons over consecutive developmental stages in behaving pups, and use dimensionality-reduction techniques to visualize stereotyped activity motifs in their population activity. We will use chronically-implanted electrodes to identify spatially-tuned activity patterns in the entorhinal cortex and hippocampus, and characterize their properties when animals are raised in sensory-poor conditions.The knowledge gathered with my projects will represent a breakthrough in our understanding of the development and function of the cognitive map, and it will provide unprecedented insight into the mechanisms driving the functional maturation of circuits located in high-end areas of cortex, where cognitive functions arise. But this proposal has the potential to go beyond basic research. Since psychological traumas and genetic dysfunctions targeting the development of higher-cognitive areas have been implicated in disorders like autism, depression, or intellectual disabilities, the experiments of this proposal will lay the foundation for a larger research vision aimed at identifying and correcting pathological deviations that have their origin in neurodevelopmental disorders.
Hippocampal circuits for the encoding of early-life memories. Research Project | 5 Project MembersThe infant brain is a formidable learning machine. But is it able to encode memories of early-life experiences? Since most of us don't remember what happened during the first years of our lives, for a long time this question has been open to debate. Recent evidence suggests that, even if we cannot recall them, early-life memories are encoded in the developing hippocampus, persist in a silent state into adulthood, and can affect the acquisition of new information later in life. We know very little about how the infant brain encodes early-life memories, despite the fact that our earliest experiences can stick with us and influence our behaviour as adults. How can the infant hippocampus produce long-lasting memory traces when its circuits are not yet mature? Why can't we remember early-life memories? And how can infant memories have long-lasting effects if we can't recall them? To answer these questions, in the following project we propose to study memory processes in the developing brain using the mouse as a model organism. We will implement a combination of genetics, viral tagging, calcium imaging, and opto- and chemogenetic methodologies, in association with behavioural paradigms, to track in vivo the activity of a large number of neurons as the brain matures, and to gain fundamental insights into the early functions of the mammalian memory system. The aims of this project are: to understand how the infant hippocampus produces neuronal ensembles to represent early-life experiences; to identify and dissect the neural circuits encoding infant memories; and to unravel how neurons supporting silent memories created during infancy influence learning processes in adults. By bridging developmental, systems, and behavioural neuroscience, our ambition is to understand how the developing brain encodes memories of early-life experiences, and how infant memories influence the operations of higher-order cognitive functions later in life.
Grid cells and the functional correlates of space in the adult brain Research Project | 4 Project MembersThe medial entorhinal cortex (MEC) supports the brain's representation of space with distinct cell types whose firing is tuned to features of the environment (grid, border, and object-vector cells) or navigation (head-direction and speed cells), and whose somata are anatomically intermingled in layer 2 of the MEC (MEC-L2). Since no single sensory stimulus can faithfully predict the firing of these cells, and activity patterns are preserved across environments and brain states, attractor network models postulate that spatially-tuned firing emerges from specific connectivity motives among neurons of the MEC. To dissect the topology of such motives, we will study how activity self-organizes in conditions in which the path integrator of MEC-L2 is able to spontaneously drift along with the connectivity matrix of the network. To this end, we will use 2-photon calcium imaging to monitor the activity of large populations of MEC-L2 neurons in head-fixed mice running on a wheel in darkness, in the absence of external sensory feedback tuned to navigation. To reveal network dynamics under these conditions, we will apply both linear and non-linear dimensionality reduction techniques to the spike matrix of each individual session. Our aim is to dissect the rules governing connectivity in the entorhinal cortex and understand how the MEC-L2 network supports the production of regular and abstract firing patterns like those of grid cells.
