ERC FUNDED PROJECTS

Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.

2 000 000 €

Start date: 2014-03-01, End date: 2019-02-28

We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.

1 638 000 €

Start date: 2009-11-01, End date: 2014-10-31

Smell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas. To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.

1 499 471 €

Start date: 2014-04-01, End date: 2019-03-31

"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."

2 375 600 €

Start date: 2013-03-01, End date: 2018-02-28

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.

1 995 000 €

Start date: 2018-03-01, End date: 2023-02-28

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.

1 500 000 €

Start date: 2018-04-01, End date: 2023-03-31

Understanding the rules and mechanisms underlying memory formation, storage and retrieval is a grand challenge in neuroscience. In light of cumulating evidence regarding non-linear dendritic events (dendritic-spikes, branch strength potentiation, temporal sequence detection etc) together with activity-dependent rewiring of the connection matrix, the classical notion of information storage via Hebbian-like changes in synaptic connections is inadequate. While more recent plasticity theories consider non-linear dendritic properties, a unifying theory of how dendrites are utilized to achieve memory coding, storing and/or retrieval is cruelly missing. Using computational models, we will simulate memory processes in three key brain regions: the hippocampus, the amygdala and the prefrontal cortex. Models will incorporate biologically constrained dendrites and state-of-the-art plasticity rules and will span different levels of abstraction, ranging from detailed biophysical single neurons and circuits to integrate-and-fire networks and abstract theoretical models. Our main goal is to dissect the role of dendrites in information processing and storage across the three different regions by systematically altering their anatomical, biophysical and plasticity properties. Findings will further our understanding of the fundamental computations supported by these structures and how these computations, reinforced by plasticity mechanisms, sub-serve memory formation and associated dysfunctions, thus opening new avenues for hypothesis driven experimentation and development of novel treatments for memory-related diseases. Identification of dendrites as the key processing units across brain regions and complexity levels will lay the foundations for a new era in computational and experimental neuroscience and serve as the basis for groundbreaking advances in the robotics and artificial intelligence fields while also having a large impact on the machine learning community.

1 398 000 €

Start date: 2012-10-01, End date: 2017-09-30

DISCRETION aims to unlock the black box of discretionary decision-making in child protection cases by a comparative-empirical study of how discretionary decisions are made and justified in the best interests of the child. There are huge research gaps in this important area of the welfare state, with a great deal of uncertainty concerning how, when and why discretionary decisions about the child´s best interests are different between decision-makers within and between child protection systems. The main objectives for this project are to reveal the mechanisms for exercising discretion, and improve the understanding of the principle of the child´s best interests. These objectives will be reached by systematically examining the role of institutional, organisational and individual factors including regulations of best interest principles; professions involved; type of courts; type of child protection system; demographic factors and individual values; and the populations’ view on children and paternalism. DISCRETION employs an innovative methodological approach, with multilevel and cross-country studies. DISCRETION will, by conducting the largest cross-national study on decision-making in child protection to date, lift our understanding of international differences in child protection to a new level. By conducting randomized survey experiments with both decision-makers in the system and the general population, DISCRETION generates unique data on the causal mechanisms explaining differences in discretionary decisions. The outcomes of DISCRETION are important because societies are at a crossroad when it comes to how children are treated and how their rights are respected, which creates tensions in the traditional relationship between the family and the state. DISCRETION will move beyond the field of child protection and provide important insights into the exercise of discretion in all areas where the public interest as well as national interest must be interpreted.

1 997 918 €

Start date: 2017-06-01, End date: 2022-05-31

As inequality increases in most developed countries, children from socioeconomically disadvantaged families are at exceptional risk for academic underachievement with lasting consequences for individuals, their communities, and society at large. Among policy makes, early childhood education and care (ECEC) is considered a key to remedy this risk. Yet the science on ECEC effectiveness at a national scale lags behind the excitement. Exploiting unique Norwegian data, we first seek to identify how and why socioeconomic disadvantage undermines children’s language skills and school achievement. Second, we will investigate whether ECEC can improve opportunities for disadvantaged children to excel. Third, to clarify the policy relevance of these inquiries, we will estimate costs of socioeconomic achievement gaps and the economic benefits of ECEC at scale. We take an investigative approach that is unprecedented in scope—from population level trends down to nuanced assessments of individual children’s growth. Throughout the 2000s, Norway’s child poverty rates increased from about 4% to 10%, while the coverage of public ECEC for toddlers increased from 30% to 80%. Across this unique window of time, we have access to rich survey data on language skills and home environment for 100,000 children, and genetically informative data, linked with administrative records on community- and family level socioeconomic risks and opportunities, and on national achievement test scores. These data allow us powerful analytic opportunities, combining state-of-the-art statistical, econometric, psychometric, and genetic epidemiological methods. I am well positioned to lead this project, having qualified for a Professorship at the University of Oslo aged 36, and having considerable experience in (a) publishing in highly respected scientific journals, (b) working at the intersection of research and policy, (c) leading research projects, and (d) mentoring younger scholars.

1 907 959 €

Start date: 2019-06-01, End date: 2024-05-31

Frontal cortical areas are responsible for a wide range of executive and cognitive functions. Frontal cortices communicate with the thalamus via bidirectional pathways and these connections are indispensable for frontal cortical operations. Still, we have very little information about the specificity of connections, synaptic interactions and plasticity between frontal cortex and thalamus and the roles of these interactions in frontal cortical functions. In the present proposal, we will test the hypothesis that frontal cortical areas developed a highly specialized connectivity pattern with the thalamus. This supports unique interactions between the cortex and the thalamus according to the specific requirements of frontal cortical activity, including experience-dependent plastic changes. The project will use cell type-specific viral tracing in mice and 3D electron microscopic reconstructions in mice and humans to identify circuit motifs that are evolutionarily conserved, yet, still specific to fronto-thalamic pathways. The physiological approach will employ in vivo optogenetics combined with intra-, juxta- and extracellular recordings. We will perform behavioral experiments by bidirectional modulation of well-defined elements in the network, in learning paradigms, which depend on the integrity of frontal cortex. The project is the first systematic approach which aims to understand the nature of interaction between the frontal cortex and the thalamus. It will not only fill the tremendous gap in our knowledge regarding these pathways but will help us elucidate the functional organization of non-sensory thalamus in general. Frontal cortices are involved in a wide range of major neurological disorders (e.g. Parkinson’s disease, epilepsy, schizophrenia, chronic pain) which affect executive functions and involve fronto-thalamic pathways. We believe that understanding fronto-thalamic interactions will lead to fundamentally novel insight into the nature of these diseases.

1 597 575 €

Start date: 2017-09-01, End date: 2022-08-31

Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.

2 498 750 €

Start date: 2018-10-01, End date: 2023-09-30

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

1 500 000 €

Start date: 2016-10-01, End date: 2021-09-30

Molecular biology strives for the prediction of function, based on the genetic code. Within neuroscience, this is reflected in the intense study of the molecular basis for ligand recognition by neurotransmitter receptors. Consequently, structural and functional studies have rendered a profoundly high-resolution view of ionotropic glutamate receptors (iGluRs), the archetypal excitatory receptor in the brain. But even this view is obsolete: we don’t know why some receptors recognize glutamate yet others recognize other ligands; and we have been unable to functionally test the underlying chemical interactions. In other words, our view differs substantially from nature’s own view of ligand recognition. I plan to lead a workgroup attacking this problem on three fronts. First, bioinformatic identification and electrophysiological characterization of a broad and representative sample of iGluRs from across the spectrum of life will unveil the diversity of ligand recognition in iGluRs. Second, phylogenetic analyses combined with functional experiments will reveal the molecular changes that nature employed in arriving at existing means of ligand recognition in iGluRs. Finally, chemical-scale mutagenesis will be employed to overcome previous technical limitations and dissect the precise chemical interactions that determine the specific recognition of certain ligands. With my experience in combining phylogenetics and functional experiments and in the use of chemical-scale mutagenesis, the objectives are within reach. Together, they form a unique approach that will expose nature’s own view of ligand recognition in iGluRs, revealing the molecular blueprint for protein function in the nervous system.

1 500 000 €

Start date: 2019-03-01, End date: 2024-02-29

Understanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.

2 287 500 €

Start date: 2017-06-01, End date: 2022-05-31

The ultimate goal of INSPIRE is to develop Transcranial Magnetic Stimulation (TMS)-based and training protocols that will improve semantic skills and creative thinking of healthy and impaired individuals by manipulating the balance between the hemispheres while they process language. Although ambitious and revolutionary, this goal is fundamental to conceptions of language processing and functional lateralization in the human brain. Specific objectives are: (1) To investigate how do semantic processes interact with creative thinking, particularly in the right hemisphere (RH). (2) To generate (reversible and temporary) localized functional impairment in healthy participants in order to specify the cortical areas involved in normal semantic processing. In particular, inhibitory TMS protocols will be used to investigate the role of the RH in processing remote associations, metaphors, sarcasm and subordinate meanings of ambiguous words. Complementary TMS-induced impairments are predicted for left hemisphere (LH) stimulation in language areas. (3) To improve RH semantic abilities and creative thinking by targeting excitatory TMS protocols at the regions of interest, and by enhancing the functioning of the homologue un-stimulated cortex with inhibitory protocols via disinhibition. (4) To improve RH semantic abilities and creative thinking by 'left' and 'right' hemisphere training. (5) To apply the research findings of objectives 1-4 above to aphasia, schizophrenia and RH brain damaged patients in order to improve their semantic skills. Prof. Lavidor is now moving back to Israel with her family after a long stay in the UK. The ERC support is requested for the re-establishment of an active and successful TMS lab in Israel, similar to the one Lavidor set up in the UK. The INSPIRE project, if funded, will allow her to build a new generation of inspired research students in her new lab, trained for excellence by Lavidor, who won the 2006 Marie Curie Excellence Award

638 400 €

Start date: 2008-10-01, End date: 2012-09-30

Aberrant protein aggregation (proteotoxicity) is an underlying mechanistic event common to numerous late-onset human neurodegenerative maladies including Alzheimer’s (AD) disease. Recent studies indicated that the ageing process plays key roles in enabling protein aggregation to become toxic late in life. The insulin/IGF signaling pathway (IIS) is a major ageing, stress resistance and lifespan regulator in worms and mice. We found that IIS reduction protects worms and mice from toxicity associated with the AD linked peptide, Aβ. These findings point to the alteration of ageing by IIS reduction as a promising research avenue towards the development of neurodegeneration therapies. In the nematode C. elegans, both effects of IIS reduction; longevity and protection from proteotoxicity are dependent on the activity of the FOXO transcription factor DAF-16. However, these functions of DAF-16/FOXO differ temporally; in worms the mediation of longevity by DAF-16 is restricted to reproductive adulthood while protection from proteotoxicity extends also to late adulthood. This differential temporal activity pattern suggests that different DAF-16 co-factors and target genes play roles in the mediation of longevity and in protection from proteotoxicity. Thus, a careful characterization of the late life DAF-16 regulated protective mechanism is required to evaluate the therapeutic potential of IIS reduction as a future treatment for neurodegenerative disorders. Here I propose to use nematodes and mice to explore the DAF-16/FOXO co-factors and target genes that mediate stress resistance and protection from proteotoxicity in the aged organism. Dual experimental approach will be utilized to achieve this goal; a directed genetic screen for the identification of co-factors and temporally differential set of DNA microarrays for the recognition of late life DAF-16/FOX target genes. This project is expected to yield new insight and to serve as a platform for future studies.

1 438 899 €

Start date: 2011-10-01, End date: 2017-09-30

How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains one of the most fundamental questions in neuroscience. Empirical and theoretical studies suggest that homeostatic negative feedback mechanisms operate to stabilize the function of a system at a set point level of activity. While extensive research uncovered diverse homeostatic mechanisms that maintain activity of neural circuits at extended timescales, several key questions remain open. First, what are the basic principles and the molecular machinery underlying invariant population dynamics of neural circuits, composed from intrinsically unstable activity patterns of individual neurons? Second, is homeostatic regulation compromised in Alzheimer's disease (AD) and do homeostatic failures lead to aberrant brain activity and memory decline, the overlapping phenotypes of AD and many other distinct neurodegenerative disorders? And finally, how do homeostatic systems operate in vivo under experience-dependent changes in firing rates and patterns? To target these questions, we have developed an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations, signaling processes at the level of single synapses and neuronal meta-plasticity. We will focus on hippocampal circuitry and combine ex vivo electrophysiology, single- and two-photon excitation imaging, time-resolved fluorescence microscopy and molecular biology, together with longitudinal monitoring of activity from large populations of hippocampal neurons in freely behaving mice. Utilizing these state-of-the-art approaches, we will determine how firing stability is maintained at different spatial scales and what are the mechanisms leading to destabilization of firing patterns in AD-related context. The proposed research will elucidate fundamental principles of neuronal function and offer conceptual insights into AD pathophysiology.

2 000 000 €

Start date: 2017-10-01, End date: 2022-09-30

Circadian (24hs) rhythms in locomotor activity are one of the best-characterized behaviors at the molecular, cellular and neural levels. Despite that, our understanding of how these rhythms are generated is still limited. A major shortcoming of the current approaches in the field is that they depict the circadian clock as a mere addition of steps (and/or combination of parts). By doing so, the circadian oscillator is portrayed as a static rather than a dynamic system. We have recently shown for the first time that miRNA-mediated regulation plays a role in circadian timekeeping in Drosophila. In the present project we will exploit complementary and cutting-edge approaches that will provide an integrative and comprehensive view of the circadian timekeeping system. As we believe that miRNAs are key mediators of this integration, we will dissect their role in the circadian clock at the molecular, cellular and neural levels in Drosophila. At the molecular level, we will determine the mechanisms, and proteins that mediate the circadian regulation of miRNAs function. Moreover, by the use of high-throughput methodology we will assess and characterize the impact of translational regulation on both the circadian transcriptome and proteome. At the cellular level, we plan to determine how this type of regulation integrates with other circadian pathways and which specific pathways and proteins mediate this process. As a final goal of the proposed project we plan to generate a complete genetic interaction map of the known circadian regulators, which will integrate the different molecular and cellular events involved in timekeeping. This will be a key step towards the understanding of the circadian clock as a dynamic adjustable process. Last, but not least, we will study the role of miRNAs in the circadian neural network. For doing so we will set up an ex vivo approach (fly brain's culture) that will assess circadian parameters through fluorescent continuous live imaging.

1 478 606 €

Start date: 2011-02-01, End date: 2016-01-31

Neuronal computations in the brain require a high metabolic budget yet the brain has extremely limited resources; calling for an on-demand, robust supply system to deliver nutrients to active regions. In most cases, neuronal activity results in an increase in blood flow to the active area, a phenomenon called functional hyperaemia. This coupling between neuronal and vascular activtuy underpins the mechanism enabling fMRI to map neuronal activity based on vascular dynamics; further, malfunction of the cellular players involved in coupling is now considered to play a key role in otherwise classically defined neurodegenerative diseases. We lack a concise description of the inner workings of this mechanism and a thorough quantitative description of the neuro-gila-vascular interface; issues that are best addressed by an investigation into the cellular mechanisms, the temporal dynamics and multi-scale spatial organization governing neurovascular coupling. My long-term goal is to provide a unified theory to encapsulate our knowledge on neurovascular coupling. Here, I hypothesize that functional hyperaemia results from the constant integration of vasoactive cues with region-dependent coupling emerging from different neuro-glia-vascular microcircuits, nuances in afferent wiring into vascular contractile elements and/or neuronal activity patterns. I will test this hypothesis with a multi-faceted correlative approach combining: two-photon awake imaging of cellular and vascular dynamics to obtain physiological data unaffected by anaesthetics; super-resolution structural imaging of intact volumes to map the fine details of micro-circuit structure; array-tomography to map in situ the neurovascular signalling machinery and novel optogenic tools to manipulate several of its specific components. I expect to offer a revolutionary mechanistic insight into one of the most basic and fundamental physiological processes behind the structure and function of the brain.

1 500 000 €

Start date: 2015-06-01, End date: 2020-05-31

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.

2 000 000 €

Start date: 2016-11-01, End date: 2021-10-31

The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.

1 280 000 €

Start date: 2008-07-01, End date: 2013-06-30

Information is represented and transmitted in the brain by the joint activity of large groups of neurons. Understanding how information is “written” in these population patterns, and how it is read and processed, is a fundamental question in neuroscience. Yet, because of the huge number of potential activity patterns and complexity of natural stimuli, most of our understanding of the code relies on single neuron studies. We will extend and apply mathematical tools from information theory, machine learning, and physics, to overcome this ‘curse of dimensionality’ and build neural dictionaries relating activity and stimuli at an unparalleled resolution of hundreds of neurons. To identify the fundamental design principles of neural population codes we will study the spatial and spatio-temporal activity of hundreds of neurons from the retina, tectum, and cortical networks responding to naturalistic and artificial stimuli. Our primary goals are: (a) to characterize the encoding ‘codebooks’ of large populations of neurons, and the effect of network noise on encoding, and thus construct a thesaurus for neural populations, (b) use this thesaurus to develop new family of decoders of population activity which would be biologically plausible and accurate for natural stimuli, (c) characterize adaptation at the level of the code of networks of neurons, and the effect of learning on population neural codes, (d) explore “learnability” as a key feature of the neural code, and construct biologically plausible models of how the brain can learn to read population codes and compute, and (e) merge these ideas into a new mathematical framework that will connect the architecture of neural interaction networks and the properties of their neural codes. Our work will establish a new mathematical framework for studying the neural code, which will entail important implications for neural prostheses and brain machine interfaces, as well as brain-inspired learning algorithms.

1 438 996 €

Start date: 2013-01-01, End date: 2018-10-31

In order to survive and maintain normal function, the cell depends on a dynamic system of spatial specificity and fidelity of signaling pathways that can respond to both internal and external changes over space and time. This cell-cell communication is mediated by ligand-receptor mechanisms. In the case of highly polarized cells such as neurons trafficking mechanisms mediated by motor proteins are used to achieve precise signal targeting. Alterations in the trafficking machinery may results in incorrect signaling, that in some cases leads to neurodegeneration. An example for such phenomenon may be found in Amyotrophic Lateral Sclerosis (ALS). ALS is a motor neuron disease characterized by a non-cell autonomous neurodegeneration process, which involves neighboring cells via an unknown mechanism. This proposal focuses on the elucidation of basic cell-cell communication mechanisms by using the motor neuron degeneration process as a model. I aim to reveal critical communication mechanisms between the neuron and its environment for cell survival and synapse maintenance. My working hypothesis is that alterations in extrinsic and intrinsic signals may lead to the neurodegeneration seen in ALS. I will develop unique compartmental platforms mimicking the natural environment of the motor neuron. Then using differential “omics” approaches followed by functional assays I will reveal and characterized vital factors essential to neuron synapse integrity and neuron survival. Using state of the art live-cell imaging techniques I will reveal also the molecular mechanism for signals localization and targeting driven by the motor protein dynein. I will elucidate the molecular mechanism of neuronal communication with its diverse environment essential to its survival and proper function. The project will bring revolutionary new mechanistic insight to a truly fundamental problem in cell biology, how the cell communicates and how signals arrive at the right place at the right time?

1 499 800 €

Start date: 2013-02-01, End date: 2019-01-31

Neurons exhibit the most marked size differences and diversity in intrinsic growth rates of any class of cells. How then can a neuron coordinate between biosynthesis rates in the soma and the growth needs of different lengths of axons? The central hypothesis of this proposal is that neurons sense the lengths of the axonal microtubule cytoskeleton on an ongoing basis by bidirectional motor-dependent axon-nucleus communication, and that the oscillating retrograde signal generated by this mechanism provides input for the coordinated regulation of neuronal biosynthesis and axonal growth. We will test this hypothesis in a multidisciplinary work program that will characterize and quantify the link between biosynthesis levels and axon outgrowth rates and identify and validate the roles and functions of key molecules underlying this mechanism. This research program will elucidate how neuronal biosynthesis and axon growth are co-regulated. New mechanistic insights on this fundamental aspect of neuronal cell biology will have far-reaching implications. From the basic science perspective, this work will establish a new modality for encoding spatial information in biological signals, providing a one-dimensional solution to the three-dimensional problem of sensing cell size. Moreover, the proposed mechanism can explain intrinsic limits on regenerative neuronal growth and raises the intriguing possibility of opening new avenues to bypass such limits towards acceleration of axonal growth for effective neural repair.

2 498 040 €

Start date: 2013-10-01, End date: 2018-09-30