Project acronym CIRCUITASSEMBLY
Project Development of functional organization of the visual circuits in mice
Researcher (PI) Keisuke Yonehara
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Summary
The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym CLAUSTRUM
Project The Claustrum: A Circuit Hub for Attention
Researcher (PI) Amihai CITRI
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Our senses face a constant barrage of information. Hence, understanding how our brain enables us to attend to relevant stimuli, while ignoring distractions, is of increasing biomedical importance. Recently, I discovered that the claustrum, a multi-sensory hub and recipient of extensive neuromodulatory input, enables resilience to distraction.
In my ERC project, I will explore the mechanisms underlying claustral mediation of resilience to distraction and develop novel approaches for assessing and modulating attention in mice, with implications for humans. Transgenic mouse models that I identified as enabling selective access to claustral neurons overcome its limiting anatomy, making the claustrum accessible to functional investigation. Using this novel genetic access, I obtained preliminary results strongly suggesting that the claustrum functions to filter distractions by adjusting cortical sensory gain.
My specific aims are: 1) To delineate the mechanisms whereby the claustrum achieves sensory gain control, by applying in-vivo cell-attached, multi-unit and fiber photometry recordings from claustral and cortical neurons during attention-demanding tasks. 2) To discriminate between the functions of the claustrum in multi-sensory integration and implementation of attention strategies, by employing multi-sensory behavioral paradigms while modulating claustral function. 3) To develop validated complementary physiological and behavioral protocols for adjusting claustral mediation of attention via neuromodulation.
This study is unique in its focus and aims: it will provide a stringent neurophysiological framework for defining a key mechanism underlying cognitive concepts of attention, and establish a novel platform for studying the function of the claustrum and manipulating its activity. The project is designed to achieve breakthroughs of fundamental nature and potentially lead to diagnostic and therapeutic advances relevant to attention disorders.
Summary
Our senses face a constant barrage of information. Hence, understanding how our brain enables us to attend to relevant stimuli, while ignoring distractions, is of increasing biomedical importance. Recently, I discovered that the claustrum, a multi-sensory hub and recipient of extensive neuromodulatory input, enables resilience to distraction.
In my ERC project, I will explore the mechanisms underlying claustral mediation of resilience to distraction and develop novel approaches for assessing and modulating attention in mice, with implications for humans. Transgenic mouse models that I identified as enabling selective access to claustral neurons overcome its limiting anatomy, making the claustrum accessible to functional investigation. Using this novel genetic access, I obtained preliminary results strongly suggesting that the claustrum functions to filter distractions by adjusting cortical sensory gain.
My specific aims are: 1) To delineate the mechanisms whereby the claustrum achieves sensory gain control, by applying in-vivo cell-attached, multi-unit and fiber photometry recordings from claustral and cortical neurons during attention-demanding tasks. 2) To discriminate between the functions of the claustrum in multi-sensory integration and implementation of attention strategies, by employing multi-sensory behavioral paradigms while modulating claustral function. 3) To develop validated complementary physiological and behavioral protocols for adjusting claustral mediation of attention via neuromodulation.
This study is unique in its focus and aims: it will provide a stringent neurophysiological framework for defining a key mechanism underlying cognitive concepts of attention, and establish a novel platform for studying the function of the claustrum and manipulating its activity. The project is designed to achieve breakthroughs of fundamental nature and potentially lead to diagnostic and therapeutic advances relevant to attention disorders.
Max ERC Funding
1 995 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym CLAUSTRUM
Project Optical interrogation of the claustrum from synapses to behavior
Researcher (PI) Adam Max PACKER
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary How does the brain integrate inputs from the environment to generate perception and drive decisions? An enigmatic brain region called the claustrum has been suggested to play a role by integrating inputs from multiple brain regions. There is strong interconnectivity between claustrum and nearly every neocortical brain region, indicating that it exerts widespread influence on brain function. However, approaches to specifically record from or manipulate activity in the claustrum have been hindered by the inability to target it selectively. This has been difficult due to the anatomy of the claustrum: it is a long, thin bilateral nucleus buried between the neocortex and the striatum. This proposal aims to understand the role of the claustrum in multisensory integration and behaviour by developing new approaches for monitoring and manipulating the activity of the claustrum. We will harness recent advances in electrophysiological, genetic, optical, and behavioural tools to probe its connectivity, activity, and function in a precise manner. Understanding the role of the claustrum in brain function will provide fundamental insight into information processing in the neocortex, which is a major goal in neuroscience. The claustrum is unique because of its dense reciprocal connectivity with neocortex but nearly complete lack of direct subcortical sensory input. This particular anatomical structure indicates the possibility of a unique function, but none has been observed yet. This proposal will rectify the paucity of data on this distinctive structure by applying a battery of modern tools to address the function of the claustrum. Experiments will address the following key questions:
1. How are claustrocortical inputs integrated and what is the effect of corticoclaustral feedback?
2. What is the activity of claustral neurons during sensory stimulation and motor output?
3. What are the causal relationships between claustrum activity and animal behaviour?
Summary
How does the brain integrate inputs from the environment to generate perception and drive decisions? An enigmatic brain region called the claustrum has been suggested to play a role by integrating inputs from multiple brain regions. There is strong interconnectivity between claustrum and nearly every neocortical brain region, indicating that it exerts widespread influence on brain function. However, approaches to specifically record from or manipulate activity in the claustrum have been hindered by the inability to target it selectively. This has been difficult due to the anatomy of the claustrum: it is a long, thin bilateral nucleus buried between the neocortex and the striatum. This proposal aims to understand the role of the claustrum in multisensory integration and behaviour by developing new approaches for monitoring and manipulating the activity of the claustrum. We will harness recent advances in electrophysiological, genetic, optical, and behavioural tools to probe its connectivity, activity, and function in a precise manner. Understanding the role of the claustrum in brain function will provide fundamental insight into information processing in the neocortex, which is a major goal in neuroscience. The claustrum is unique because of its dense reciprocal connectivity with neocortex but nearly complete lack of direct subcortical sensory input. This particular anatomical structure indicates the possibility of a unique function, but none has been observed yet. This proposal will rectify the paucity of data on this distinctive structure by applying a battery of modern tools to address the function of the claustrum. Experiments will address the following key questions:
1. How are claustrocortical inputs integrated and what is the effect of corticoclaustral feedback?
2. What is the activity of claustral neurons during sensory stimulation and motor output?
3. What are the causal relationships between claustrum activity and animal behaviour?
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym Clock Mechanics
Project Mechanosensation and the circadian clock: a reciprocal analysis
Researcher (PI) Joerg Albert
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time.
Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.
Summary
All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time.
Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.
Max ERC Funding
1 899 549 €
Duration
Start date: 2015-09-01, End date: 2021-08-31
Project acronym CLUE-BGD
Project Closing the Loop between Understanding and Effective Treatment of the Basal Ganglia and their Disorders
Researcher (PI) Hagai Bergman
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Summary
In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Max ERC Funding
2 476 922 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CMTaaRS
Project Defective protein translation as a pathogenic mechanism of peripheral neuropathy
Researcher (PI) Erik Jan Marthe STORKEBAUM
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism.
In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model.
I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.
Summary
Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism.
In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model.
I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CN Identity
Project Comprehensive anatomical, genetic and functional identification of cerebellar nuclei neurons and their roles in sensorimotor tasks
Researcher (PI) Zhenyu Gao
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS5, ERC-2019-STG
Summary How does the brain integrate diverse sensory inputs and generate appropriate motor commands? Our cerebellum is a key region for such a sensorimotor processing, empowered by its sophisticated neural computation and constant communication with other brain regions. The well-timed cerebellar information is integrated and funneled to other brain regions through the cerebellar nuclei (CN). Yet, how CN circuitry contributes to the cerebellar control of sensorimotor processing is unclear. My recent work indicates that the CN activity serves various functions ranging from the online motor control, the amplitude amplification of cerebellar outputs to the control of motor planning. Given these advances, I am now in a unique position to decipher the properties of CN neurons and identify their specific roles in different forms of sensorimotor processing. It is my central hypothesis that depending on the specific demands of the task, CN neurons can either facilitate or suppress the activity of downstream regions with millisecond precision; and the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this hypothesis, I will 1) identify the activity patterns of different CN modules during the acquisition and execution of two sensorimotor tasks and characterize the relevant extra-cerebellar inputs to these modules; 2) identify the connectivity-transcription logic of different CN modules and link them to their task-specific outputs; and 3) examine the impacts of manipulating anatomically and/or genetically defined CN neurons on the downstream regions during different sensorimotor tasks. I will accomplish these key objectives by developing various novel electrophysiological, optogenetic, molecular and imaging techniques. My research is likely to break new ground, demonstrating that the identity of CN neurons is determined by their differential temporal demands of sensorimotor tasks controlled by different brain structures.
Summary
How does the brain integrate diverse sensory inputs and generate appropriate motor commands? Our cerebellum is a key region for such a sensorimotor processing, empowered by its sophisticated neural computation and constant communication with other brain regions. The well-timed cerebellar information is integrated and funneled to other brain regions through the cerebellar nuclei (CN). Yet, how CN circuitry contributes to the cerebellar control of sensorimotor processing is unclear. My recent work indicates that the CN activity serves various functions ranging from the online motor control, the amplitude amplification of cerebellar outputs to the control of motor planning. Given these advances, I am now in a unique position to decipher the properties of CN neurons and identify their specific roles in different forms of sensorimotor processing. It is my central hypothesis that depending on the specific demands of the task, CN neurons can either facilitate or suppress the activity of downstream regions with millisecond precision; and the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this hypothesis, I will 1) identify the activity patterns of different CN modules during the acquisition and execution of two sensorimotor tasks and characterize the relevant extra-cerebellar inputs to these modules; 2) identify the connectivity-transcription logic of different CN modules and link them to their task-specific outputs; and 3) examine the impacts of manipulating anatomically and/or genetically defined CN neurons on the downstream regions during different sensorimotor tasks. I will accomplish these key objectives by developing various novel electrophysiological, optogenetic, molecular and imaging techniques. My research is likely to break new ground, demonstrating that the identity of CN neurons is determined by their differential temporal demands of sensorimotor tasks controlled by different brain structures.
Max ERC Funding
1 400 000 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym CODE4Vision
Project Computational Dissection of Effective Circuitry and Encoding in the Retina for Normal and Restored Vision
Researcher (PI) Tim Gollisch
Host Institution (HI) UNIVERSITAETSMEDIZIN GOETTINGEN - GEORG-AUGUST-UNIVERSITAET GOETTINGEN - STIFTUNG OEFFENTLICHEN RECHTS
Call Details Consolidator Grant (CoG), LS5, ERC-2016-COG
Summary Understanding how neural circuits process and encode information is a fundamental goal in neuroscience. For the neural network of the retina, such knowledge is also of concrete importance for the development of vision restoration therapies for patients suffering from degeneration of photoreceptors. Artificial stimulation of retinal neurons through electronic implants or inserted light-sensitive proteins (“optogenetics”) aims at reconstructing natural transmission of visual information to the brain. Recreating natural retinal activity, however, will require a thorough understanding of the complex and diverse neural code of the retina. The challenge lies in deciphering the various nonlinear operations and dynamics in the around 30 parallel signalling streams that emerge from the retina, represented by as many types of ganglion cells, the retina’s output neurons.
The CODE4Vision project will tackle this challenge by identifying the effective connectivity between the different types of retinal ganglion cells and their excitatory presynaptic partners, bipolar cells, and by determining the features of information processing between these neuronal layers. We will characterize the layout of bipolar cell inputs to large populations of ganglion cells with novel analyses that we derive from computational statistics and machine learning. We will then study the nonlinear and dynamical features of these connections by designing closed-loop experiments that automatically adjust visual stimuli to the identified layout of bipolar cells. These analyses will be supplemented by direct measurements of connections through simultaneous bipolar and ganglion cell recordings. The results will pave the way towards new models of how the retina encodes natural visual stimuli. Finally, we will apply this knowledge to mouse models of optogenetic vision restoration in order to develop stimulation schemes that emulate natural retinal stimulus encoding.
Summary
Understanding how neural circuits process and encode information is a fundamental goal in neuroscience. For the neural network of the retina, such knowledge is also of concrete importance for the development of vision restoration therapies for patients suffering from degeneration of photoreceptors. Artificial stimulation of retinal neurons through electronic implants or inserted light-sensitive proteins (“optogenetics”) aims at reconstructing natural transmission of visual information to the brain. Recreating natural retinal activity, however, will require a thorough understanding of the complex and diverse neural code of the retina. The challenge lies in deciphering the various nonlinear operations and dynamics in the around 30 parallel signalling streams that emerge from the retina, represented by as many types of ganglion cells, the retina’s output neurons.
The CODE4Vision project will tackle this challenge by identifying the effective connectivity between the different types of retinal ganglion cells and their excitatory presynaptic partners, bipolar cells, and by determining the features of information processing between these neuronal layers. We will characterize the layout of bipolar cell inputs to large populations of ganglion cells with novel analyses that we derive from computational statistics and machine learning. We will then study the nonlinear and dynamical features of these connections by designing closed-loop experiments that automatically adjust visual stimuli to the identified layout of bipolar cells. These analyses will be supplemented by direct measurements of connections through simultaneous bipolar and ganglion cell recordings. The results will pave the way towards new models of how the retina encodes natural visual stimuli. Finally, we will apply this knowledge to mouse models of optogenetic vision restoration in order to develop stimulation schemes that emulate natural retinal stimulus encoding.
Max ERC Funding
1 991 445 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym COFBMIX
Project Cortical feedback in figure background segregation of odors.
Researcher (PI) Dan ROKNI
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2017-STG
Summary A key question in neuroscience is how information is processed by sensory systems to guide behavior. Most of our knowledge about sensory processing is based on presentation of simple isolated stimuli and recording corresponding neural activity in relevant brain areas. Yet sensory stimuli in real life are never isolated and typically not simple. How the brain processes complex stimuli, simultaneously arising from multiple objects is unknown. Our daily experience (as well as well-controlled experiments) shows that only parts of a complex sensory scene can be perceived - we cannot listen to more than one speaker in a party. Importantly, one can easily choose what is important and should be processed and what can be ignored as background. These observations lead to the prevalent hypothesis that feedback projections from ‘higher’ brain areas to more peripheral sensory areas are involved in processing of complex stimuli. However experimental analysis of signals conveyed by feedback projections in behaving animals is scarce. The nature of these signals and how they relate to behavior is unknown.
Here I propose a cutting edge approach to directly record feedback signals in the olfactory system of behaving mice. We will use chronically implanted electrodes to record the modulation of olfactory bulb (OB) principal neurons by task related context. Additionally, we will record from piriform cortical (PC) neurons that project back to the OB. These will be tagged with channelrhodopsin-2 and identified by light sensitivity. Finally, we will express the spectrally distinct Ca++ indicators GCaMP6 and RCaMP2 in PC neurons and in olfactory sensory neurons, respectively, and use 2-photon microscopy to analyze the spatio-temporal relationship between feedforward and feedback inputs in the OB. This comprehensive approach will provide an explanation of how feedforward and feedback inputs are integrated to process complex stimuli.
Summary
A key question in neuroscience is how information is processed by sensory systems to guide behavior. Most of our knowledge about sensory processing is based on presentation of simple isolated stimuli and recording corresponding neural activity in relevant brain areas. Yet sensory stimuli in real life are never isolated and typically not simple. How the brain processes complex stimuli, simultaneously arising from multiple objects is unknown. Our daily experience (as well as well-controlled experiments) shows that only parts of a complex sensory scene can be perceived - we cannot listen to more than one speaker in a party. Importantly, one can easily choose what is important and should be processed and what can be ignored as background. These observations lead to the prevalent hypothesis that feedback projections from ‘higher’ brain areas to more peripheral sensory areas are involved in processing of complex stimuli. However experimental analysis of signals conveyed by feedback projections in behaving animals is scarce. The nature of these signals and how they relate to behavior is unknown.
Here I propose a cutting edge approach to directly record feedback signals in the olfactory system of behaving mice. We will use chronically implanted electrodes to record the modulation of olfactory bulb (OB) principal neurons by task related context. Additionally, we will record from piriform cortical (PC) neurons that project back to the OB. These will be tagged with channelrhodopsin-2 and identified by light sensitivity. Finally, we will express the spectrally distinct Ca++ indicators GCaMP6 and RCaMP2 in PC neurons and in olfactory sensory neurons, respectively, and use 2-photon microscopy to analyze the spatio-temporal relationship between feedforward and feedback inputs in the OB. This comprehensive approach will provide an explanation of how feedforward and feedback inputs are integrated to process complex stimuli.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym COGNIBRAINS
Project Cognition in an Insect Brain
Researcher (PI) Martin GIURFA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Summary
There is a common perception that larger brains mediate higher cognitive capacity. Social insects, however, demonstrate that sophisticated cognition is possible with miniature brains. Honeybees display higher-order learning such as categorization, non-linear discriminations, concept learning and numerosity, which are unique among insects. These capacities are mediated by a miniature brain with only 950 000 neurons. Despite extensive behavioral analyses, no study has attempted to elucidate the neural mechanisms underpinning the higher-order learning of bees. Our current breakthrough establishing virtual-reality protocols for tethered honeybees offers a unique opportunity to uncover the minimal circuits that mediate higher-order forms of cognitive processing in the brain of a behaving bee. We have recently shown that bees learn to solve elemental and non-elemental problems in this experimental context, which allows integrating behavioral, neurobiological and computational approaches to unravel the neural mechanisms underlying non-elemental learning in the honeybee. I will combine behavioral recordings of bees learning non-linear discriminations and relational rules in a virtual reality environment, with access to their brain via multi-photon calcium imaging and multielectrode recordings of neural populations. I will determine the neural circuits of elemental and non-elemental visual learning along the visual circuits of the bee brain, and the necessity and sufficiency of these circuits for these capacities via selective knockdown and rescuing via wavelength-selective multi-photon uncaging of neurotransmitters. Data will be fed into computational models to test hypotheses about minimal neural architectures for visual cognition, working towards whole-brain modeling. This project will expand the information available on the neurobiology of insect learning, and will provide the first integral characterization of the mechanisms underlying cognition in a miniature brain.
Max ERC Funding
2 145 339 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
