Project acronym GutBCells
Project Cellular Dynamics of Intestinal Antibody-Mediated Immune Response
Researcher (PI) Ziv Shulman Ben-Avraham
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE LTD
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Vaccination is widely used to prevent human diseases by inducing the formation of cellular and antibody-mediated immune responses for induction of long lasting immunological memory. Although most studies focus on immune responses elicited against injected immunizations, the simplest delivery of a vaccine regimen is by oral administration. The cellular and molecular components of the antibody immune response in peripheral lymph nodes in response to immunization are well described, however, much less is known about the dynamics of immune cells in gut associate lymphoid tissues (GALT) and adjust intestinal mucosal tissues. In the proposed research plan I will implicate intravital in vivo imaging for analysis of the cellular component of the antibody immune response in intestinal tissues. My goals are: 1. To track germinal center (GC) T cells for prolong time periods in peripheral lymph nodes and GALT and determine if they enter the memory compartment. For this purpose I will develop a new photoactivation method for permanently labeling immune cells and fate tracing of their daughter cells. 2. To examine T-B interactions and their regulation by intraceullar signaling pathways in GALT and to determine where and when class switch recombination to IgA takes place. For this purpose I will use intravital imaging of fluorescent reporter mice. 3. I will analyze the dynamics of plasma cell migration from Peyer’s patches to the mucosa by implementing state of the art photoactivation and imaging techniques that allow prolonged cell tracking. I will also use photoactivation approaches for sorting plasma cells from specific intestinal layers and perform gene expression analysis. 4. I will develop a new method to study dynamics and fate of B cells specific for commensal microbes in the GC, memory and plasma cell compartments. This research plan will extend our knowledge of the antibody immune response in intestinal tissues towards the future design of improved oral vaccinations.
Summary
Vaccination is widely used to prevent human diseases by inducing the formation of cellular and antibody-mediated immune responses for induction of long lasting immunological memory. Although most studies focus on immune responses elicited against injected immunizations, the simplest delivery of a vaccine regimen is by oral administration. The cellular and molecular components of the antibody immune response in peripheral lymph nodes in response to immunization are well described, however, much less is known about the dynamics of immune cells in gut associate lymphoid tissues (GALT) and adjust intestinal mucosal tissues. In the proposed research plan I will implicate intravital in vivo imaging for analysis of the cellular component of the antibody immune response in intestinal tissues. My goals are: 1. To track germinal center (GC) T cells for prolong time periods in peripheral lymph nodes and GALT and determine if they enter the memory compartment. For this purpose I will develop a new photoactivation method for permanently labeling immune cells and fate tracing of their daughter cells. 2. To examine T-B interactions and their regulation by intraceullar signaling pathways in GALT and to determine where and when class switch recombination to IgA takes place. For this purpose I will use intravital imaging of fluorescent reporter mice. 3. I will analyze the dynamics of plasma cell migration from Peyer’s patches to the mucosa by implementing state of the art photoactivation and imaging techniques that allow prolonged cell tracking. I will also use photoactivation approaches for sorting plasma cells from specific intestinal layers and perform gene expression analysis. 4. I will develop a new method to study dynamics and fate of B cells specific for commensal microbes in the GC, memory and plasma cell compartments. This research plan will extend our knowledge of the antibody immune response in intestinal tissues towards the future design of improved oral vaccinations.
Max ERC Funding
1 375 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym HIRESMEMMANIP
Project Spiking network mechanisms underlying short term memory
Researcher (PI) Eran Stark
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), LS5, ERC-2015-STG
Summary Short term memory (STM) is impaired at old age and a host of neuropsychiatric disorders, and has been the focus of a multitude of psychological and theoretical studies. However, the underlying neuronal circuit mechanisms remain elusive, mainly due to the lack of experimental tools: we suggest that rapid manipulations at the neuronal level are required for deciphering underlying mechanisms. We have developed an approach combining large-scale extracellular recordings and high density multi-site/multi-color optical stimulation (“diode-probes”), which enables high resolution closed-loop manipulation of multiple circuit elements in intact, free, behaving rodents. After training mice and rats to perform bridging-free STM-tasks, we will evaluate local circuit mechanisms in hippocampus and prefrontal cortex. Two broad classes of manipulations will be used: First, necessary components and timescales needed for STM maintenance will be established by focal real-time silencing of specific cell types and real-time jittering of spiking in those cells. Second, sufficient components (neuronal codes) will be determined by a circuit-training phase, in which novel associations between synthetic brain patterns and behaviorally-relevant short-term memory traces will be established. The first class is equivalent to erasing memories and the second to their writing. Together, these manipulations are expected to reveal global and local circuit mechanisms that facilitate STM maintenance in intact animals
Summary
Short term memory (STM) is impaired at old age and a host of neuropsychiatric disorders, and has been the focus of a multitude of psychological and theoretical studies. However, the underlying neuronal circuit mechanisms remain elusive, mainly due to the lack of experimental tools: we suggest that rapid manipulations at the neuronal level are required for deciphering underlying mechanisms. We have developed an approach combining large-scale extracellular recordings and high density multi-site/multi-color optical stimulation (“diode-probes”), which enables high resolution closed-loop manipulation of multiple circuit elements in intact, free, behaving rodents. After training mice and rats to perform bridging-free STM-tasks, we will evaluate local circuit mechanisms in hippocampus and prefrontal cortex. Two broad classes of manipulations will be used: First, necessary components and timescales needed for STM maintenance will be established by focal real-time silencing of specific cell types and real-time jittering of spiking in those cells. Second, sufficient components (neuronal codes) will be determined by a circuit-training phase, in which novel associations between synthetic brain patterns and behaviorally-relevant short-term memory traces will be established. The first class is equivalent to erasing memories and the second to their writing. Together, these manipulations are expected to reveal global and local circuit mechanisms that facilitate STM maintenance in intact animals
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym NATURAL_BAT_NAV
Project Neural basis of natural navigation: Representation of goals, 3-D spaces and 1-km distances in the bat hippocampal formation – the role of experience
Researcher (PI) Nachum Ulanovsky
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary The mammalian hippocampal formation contains place cells, grid cells, head-direction cells and border cells, which collectively represent the animal’s position (‘map’), distance traveled (‘odometer’) and direction (‘compass’), and are thought to underlie navigation. These neurons are typically studied in rodents running on linear tracks or in small empty boxes, ~1×1 m in size. However, real-world navigation differs dramatically from typical laboratory setups, in at least three ways – which we plan to study:
(1) The world is not empty, but contains objects and goals. Almost nothing is known about how neural circuits represent goal location – which is essential for navigating towards the goal. We will record single-neuron activity in bats flying towards spatial goals, in search for cells that encode vectorial information about the direction and distance to the goal. Preliminary results support the existence of such cells in the bat hippocampal formation. This new functional cell class of vectorial goal-encoding neurons may underlie goal-directed navigation.
(2) The world is not flat, but three-dimensional (3-D). We will train bats to fly in a large flight-room and examine 3-D grid cells and 3-D border cells.
(3) The world is not 1-m in size, and both rodents and bats navigate over kilometer-scale distances. Nothing is known about how the brain supports such real-life navigation. We will utilize a 1-km long test facility at the Weizmann Institute of Science, and record place cells and grid cells in bats navigating over biologically relevant spatial scales. Further, we will compare neural codes for space in wild-born bats versus bats born in the lab – which have never experienced a 1-km distance – to illuminate the role of experience in mammalian spatial cognition.
Taken together, this set of studies will bridge the gap – a conceptual gap and a gap in spatial scale – between hippocampal laboratory studies and real-world natural navigation.
Summary
The mammalian hippocampal formation contains place cells, grid cells, head-direction cells and border cells, which collectively represent the animal’s position (‘map’), distance traveled (‘odometer’) and direction (‘compass’), and are thought to underlie navigation. These neurons are typically studied in rodents running on linear tracks or in small empty boxes, ~1×1 m in size. However, real-world navigation differs dramatically from typical laboratory setups, in at least three ways – which we plan to study:
(1) The world is not empty, but contains objects and goals. Almost nothing is known about how neural circuits represent goal location – which is essential for navigating towards the goal. We will record single-neuron activity in bats flying towards spatial goals, in search for cells that encode vectorial information about the direction and distance to the goal. Preliminary results support the existence of such cells in the bat hippocampal formation. This new functional cell class of vectorial goal-encoding neurons may underlie goal-directed navigation.
(2) The world is not flat, but three-dimensional (3-D). We will train bats to fly in a large flight-room and examine 3-D grid cells and 3-D border cells.
(3) The world is not 1-m in size, and both rodents and bats navigate over kilometer-scale distances. Nothing is known about how the brain supports such real-life navigation. We will utilize a 1-km long test facility at the Weizmann Institute of Science, and record place cells and grid cells in bats navigating over biologically relevant spatial scales. Further, we will compare neural codes for space in wild-born bats versus bats born in the lab – which have never experienced a 1-km distance – to illuminate the role of experience in mammalian spatial cognition.
Taken together, this set of studies will bridge the gap – a conceptual gap and a gap in spatial scale – between hippocampal laboratory studies and real-world natural navigation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym Temporal Coding
Project Do behaving animals extract information from precise spike timing? – The use of temporal codes
Researcher (PI) Moshe Parnas
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), LS5, ERC-2015-STG
Summary Neural temporal codes have come to dominate our way of thinking on how information is coded in the brain. When precise spike timing is found to carry information, the neural code is defined as a temporal code. In spite of the importance of temporal codes, whether behaving animals actually use this type of coding is still an unresolved question. To date studying temporal codes was technically impossible due to the inability to manipulate spike timing in behaving animals. However, very recent developments in optogenetics solved this problem. Despite these modern tools, this key question is very difficult to resolve in mammals, because the meaning of manipulating a part of a neural circuit without knowledge of the neural activity of all the neurons involved in the coding is unclear.
The fly is an ideal model system to study temporal codes because its small number of neurons allows for complete mapping of the neural activity of all the neurons involved. Since temporal codes are suggested to be involved in olfactory intensity coding, I will study this process. I will device a multidisciplinary approach of electrophysiology, two-photon imaging and behavior.
I aim to examine for the first time directly whether temporal coding is used by behaving animals and to unravel the circuits and mechanisms that underlie intensity coding. To do so, I will manipulate the temporal codes in behaving animals and examine whether the behavioral responses change accordingly. To guide this study I will generate three novel databases of: i. the temporal activity of all neurons involved in Drosophila olfactory intensity coding. ii. The functional connectivity between the two brain regions that are involved in the intensity coding and iii. behavioral responses to different odors and intensities.
Thus, this research will use cutting edge techniques to resolve a long standing basic question in neuroscience: how does the brain actually code information?
Summary
Neural temporal codes have come to dominate our way of thinking on how information is coded in the brain. When precise spike timing is found to carry information, the neural code is defined as a temporal code. In spite of the importance of temporal codes, whether behaving animals actually use this type of coding is still an unresolved question. To date studying temporal codes was technically impossible due to the inability to manipulate spike timing in behaving animals. However, very recent developments in optogenetics solved this problem. Despite these modern tools, this key question is very difficult to resolve in mammals, because the meaning of manipulating a part of a neural circuit without knowledge of the neural activity of all the neurons involved in the coding is unclear.
The fly is an ideal model system to study temporal codes because its small number of neurons allows for complete mapping of the neural activity of all the neurons involved. Since temporal codes are suggested to be involved in olfactory intensity coding, I will study this process. I will device a multidisciplinary approach of electrophysiology, two-photon imaging and behavior.
I aim to examine for the first time directly whether temporal coding is used by behaving animals and to unravel the circuits and mechanisms that underlie intensity coding. To do so, I will manipulate the temporal codes in behaving animals and examine whether the behavioral responses change accordingly. To guide this study I will generate three novel databases of: i. the temporal activity of all neurons involved in Drosophila olfactory intensity coding. ii. The functional connectivity between the two brain regions that are involved in the intensity coding and iii. behavioral responses to different odors and intensities.
Thus, this research will use cutting edge techniques to resolve a long standing basic question in neuroscience: how does the brain actually code information?
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym TOPO-NW
Project VISUALIZATION OF TOPOLGICAL STATES IN PRISTINE NANOWIRES
Researcher (PI) Haim Beidenkopf
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), PE3, ERC-2015-STG
Summary Topological phases of matter have been at the center of intense scientific research. Over the past decade this has led to the discovery of dozens of topological materials with exotic boundary states. In three dimensional topological phases, scanning tunneling microscopy (STM) has been instrumental in unveiling the unusual properties of these surface states. This success, however, did not encompass lower dimensional topological systems. The main reason is surface contamination which is disruptive both for STM and for the fragile electronic states. We propose to study topological states of matter in pristine epitaxial nanowires by combining growth, fabrication and STM, all in a single modular ultra-high vacuum space. This platform will uniquely allow us to observe well anticipated topological phenomena in one dimension such as the Majorana end-modes in semiconducting nanowires. On a broader view, the nanowire configuration intertwines dimensionality and geometry with topology giving rise to novel topological systems with high tunability. A vivid instance is given by topological crystalline insulator nanowires in which the topological symmetry protection can be broken by a variety of perturbations. We will selectively tune the surface states band structure and study the local response of massless and massive surface Dirac electrons. Tunability provides a higher degree of control. We will utilize this to realize topological nanowire-based electronic and spintronic devices such as a Z2 pump and spin-based Mach-Zehnder interferometer for Dirac electrons. The low dimensionality of the nanowire alongside various singularities in the electronic spectra of different topological phases enhance interaction effects, serving as a cradle for novel correlated topological states. This new paradigm of topological nanowires will allow us to elucidate deep notions in topological matter as well as to explore new concepts and novel states, thus providing ample experimental prospects.
Summary
Topological phases of matter have been at the center of intense scientific research. Over the past decade this has led to the discovery of dozens of topological materials with exotic boundary states. In three dimensional topological phases, scanning tunneling microscopy (STM) has been instrumental in unveiling the unusual properties of these surface states. This success, however, did not encompass lower dimensional topological systems. The main reason is surface contamination which is disruptive both for STM and for the fragile electronic states. We propose to study topological states of matter in pristine epitaxial nanowires by combining growth, fabrication and STM, all in a single modular ultra-high vacuum space. This platform will uniquely allow us to observe well anticipated topological phenomena in one dimension such as the Majorana end-modes in semiconducting nanowires. On a broader view, the nanowire configuration intertwines dimensionality and geometry with topology giving rise to novel topological systems with high tunability. A vivid instance is given by topological crystalline insulator nanowires in which the topological symmetry protection can be broken by a variety of perturbations. We will selectively tune the surface states band structure and study the local response of massless and massive surface Dirac electrons. Tunability provides a higher degree of control. We will utilize this to realize topological nanowire-based electronic and spintronic devices such as a Z2 pump and spin-based Mach-Zehnder interferometer for Dirac electrons. The low dimensionality of the nanowire alongside various singularities in the electronic spectra of different topological phases enhance interaction effects, serving as a cradle for novel correlated topological states. This new paradigm of topological nanowires will allow us to elucidate deep notions in topological matter as well as to explore new concepts and novel states, thus providing ample experimental prospects.
Max ERC Funding
1 750 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
