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

The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression. Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.

1 500 000 €

Start date: 2011-04-01, End date: 2016-03-31

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

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

Studies of spatial navigation and neural codes for space have followed two parallel tracks over the last 100 years: One research approach was to study animal navigation in the wild over large spatial scales (kilometers); this approach focused on non-mammalian species and on behavioral studies, with hardly any research on the underlying brain mechanisms. The other approach was to study the navigation of mammals (mostly rats) in mazes and small arenas; this approach revealed 'place cells' in the hippocampus, neurons that become active at specific locations; and 'grid cells' in entorhinal cortex – neurons that respond when the animal passes through the vertices of a hexagonal grid spanning the entire environment. However, it is unknown whether place- and grid-cells are relevant at all to large-scale navigation over kilometers. Thus, there is a large gap between the two parallel approaches to studying spatial memory and navigation – both a conceptual gap, and a gap in spatial scale. Here, we propose to bridge this gap, by recording from place cells and grid cells in a flying mammal – the bat – while it moves in 4 different environments of varying sizes, from centimeters to kilometers. We will conduct both standard (tethered) and wireless neural recordings, and will also pioneer the development of a novel sonar-based virtual reality system for studying large-scale navigation. The same neurons will be recorded across different spatial scales, which will allow comparing various neural-coding schemes. These new setups will allow the first testing for the existence of kilometer-sized hippocampal place-fields and entorhinal grids, in bats navigating through naturalistic virtual landscapes; they will also provide rich information on neural codes for 2-D and 3-D space in the mammalian brain. Our innovative project is expected to provide – for the first time – a true understanding of the brain mechanisms of large-scale, realistic navigation in complex 3-D environments.

1 499 999 €

Start date: 2011-11-01, End date: 2016-10-31

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

The neocortex is organized into neural circuits that perform distinct computations, from sensory processing and motor control to memory, learning and language. Neuromodulatory systems projecting to the neocortex exert a powerful influence on cortical computations through neurotransmitters such as acetylcholine, monoamines and neuropeptides. The prefrontal cortex (PFC), a cortical region required for working memory, attention and goal-directed behavior, receives dense projections from multiple neuromodulatory systems that dramatically impact its function. Pioneering work has shown that pharmacological manipulation of these systems can potently modulate attention and cognitive function and that impaired neuromodulation can lead to psychiatric disease. Yet, much of the view of high level cortical function is focused on models that either ignore neuromodulation altogether or treat it as a reward or arousal signal. We propose to elucidate the dynamics and mechanisms of prefrontal neuromodulatory tuning, from the level of synapses and cells to circuits and animal behavior. To achieve this goal, we will map the circuit-level impact of synaptic neuromodulatory inputs on the prefrontal cortex circuit dynamics, develop and apply two novel optogenetic approaches for light-based synaptic silencing and optical recording of cortical neuromodulatory activity in vivo, and establish the causal roles of PFC neuromodulation in attention and working memory. These experiments will enable us for the first time to delineate the specific contribution of distinct neuromodulatory systems to prefrontal function, integrating comprehensive cell- and circuit-level analysis with unique opto-physiological readouts in behaving animals. The project will yield an integrative view of prefrontal neuromodulation, revealing its impact on cortical function and dissecting its roles in cognitive function.

1 429 460 €

Start date: 2014-02-01, End date: 2019-01-31

An electoral system is an essential component of representative democracy. It translates preferences of citizens to a legislative body and inevitably distorts preferences, voicing some more loudly than others. Theorizing and empirically analyzing how the electoral system tilts the playing ground is the aim of this study. The number of seats allotted to an electoral district—the district magnitude (DM)—is perhaps the most important component defining an electoral system. It is long established that DM affects key features of the political landscape in a country, such as representation, the number of parties, the type of government (single- or multi-party coalition), parties’ strategy, voters’ consideration, and even redistribution policy. Most democracies, however, have districts of many different magnitudes, and the range often reaches thirty seats gap between the smallest and largest districts in a country. Districts in Portugal, for instance, vary between two and forty-eight seats, and in Switzerland between one and thirty-five. The voluminous literature on electoral districts uniformly sidesteps this heterogeneity, focusing instead on a single middle district per country. The proposed study is the first large-scale study that theorizes about and empirically analyzes the effects of within-country district structure. I address questions such as: how does district heterogeneity shape representation at the national level? How does it affect the party system? And how does it affect party coordination? In the first part of the study I will theorize about various aspects of district heterogeneity in a country (e.g., skewness, effective number of magnitudes). I will gain deep understanding for district distributions and develop politically-relevant measures of heterogeneity. Drawing on insights from the theoretical part, the second part will empirically examine how district heterogeneity affects the political landscape, and in particular representation, party system, and party coordination. This part relies on extensive district- and national-level data collection and data analysis in OECD countries as well as in-depth case analysis. Analyzing the effect of district heterogeneity on representation, party systems, and party coordination will open new avenues of research about design of electoral systems.

1 038 686 €

Start date: 2010-11-01, End date: 2016-10-31