ERC FUNDED PROJECTS

Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.

2 486 074 €

Start date: 2016-01-01, End date: 2020-12-31

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations: - First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37); - Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells (Turk et al.,Cancer Res, 2009. 69(21)); - Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15); - Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204). I propose a comprehensive series of studies that will address thefollowing critical questions: - First, what is the scope of MDR-selective compounds? - Second, what is their mechanism of action? - Third, what is the optimal therapeutic modality? Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

1 499 640 €

Start date: 2012-01-01, End date: 2016-12-31

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

Europe sits uncomfortably on the idea that there are no political and cultural alternatives credible enough to respond to the current uneasiness or malaise caused by both a world that is more and more non-European and a Europe that increasingly questions what is European about itself. This project will develop a new grounded theoretical paradigm for contemporary Europe based on two key ideas: the understanding of the world by far exceeds the European understanding of the world; social, political and institutional transformation in Europe may benefit from innovations taking place in regions and countries with which Europe is increasingly interdependent. I will pursue this objective focusing on four main interconnected topics: democratizing democracy, intercultural constitutionalism, the other economy, human rights (right to health in particular). In a sense that the European challenges are unique but, in one way or another, are being experienced in different corners of the world. The novelty resides in bringing new ideas and experiences into the European conversation, show their relevance to our current uncertainties and aspirations and thereby contribute to face them with new intellectual and political resources. The usefulness and relevance of non-European conceptions and experiences un-thinking the conventional knowledge through two epistemological devices I have developed: the ecology of knowledges and intercultural translation. By resorting to them I will show that there are alternatives but they cannot be made credible and powerful if we go on relying on the modes of theoretical and political thinking that have dominated so far. In other words, the claim put forward by and worked through this project is that in Europe we don’t need alternatives but rather an alternative thinking of alternatives.

2 423 140 €

Start date: 2011-07-01, End date: 2016-12-31

New generations of devices for tissue engineering (TE) should rationalize better the physical and biochemical cues operating in tandem during native regeneration, in particular at the scale/organizational-level of the stem cell niche. The understanding and the deconstruction of these factors (e.g. multiple cell types exchanging both paracrine and direct signals, structural and chemical arrangement of the extra-cellular matrix, mechanical signals…) should be then incorporated into the design of truly biomimetic biomaterials. ATLAS proposes rather unique toolboxes combining smart biomaterials and cells for the ground-breaking advances of engineering fully time-self-regulated complex 2D and 3D devices, able to adjust the cascade of processes leading to faster high-quality new tissue formation with minimum pre-processing of cells. Versatile biomaterials based on marine-origin macromolecules will be used, namely in the supramolecular assembly of instructive multilayers as nanostratified building-blocks for engineer such structures. The backbone of these biopolymers will be equipped with a variety of (bio)chemical elements permitting: post-processing chemistry and micro-patterning, specific/non-specific cell attachment, and cell-controlled degradation. Aiming at being applied in bone TE, ATLAS will integrate cells from different units of tissue physiology, namely bone and hematopoietic basic elements and consider the interactions between the immune and skeletal systems. These ingredients will permit to architect innovative films with high-level dialogue control with cells, but in particular sophisticated quasi-closed 3D capsules able to compartmentalise such components in a “globe-like” organization, providing local and long-range order for in vitro microtissue development and function. Such hybrid devices could be used in more generalised front-edge applications, including as disease models for drug discovery or test new therapies in vitro.

2 498 988 €

Start date: 2015-12-01, End date: 2020-11-30

The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.

1 618 750 €

Start date: 2016-09-01, End date: 2021-08-31

"This proposal outlines projects to develop robust and portable theories studying the impact of psychological phenomena in economic settings. The proposed work falls in three broad research agendas. My first main agenda is to formally model and economically apply a simple observation: that when people make decisions, they do not focus equally on all attributes of their available options, and overweight the attributes they focus on. I will build a set of portable models of focusing in attribute-based choice and risky choice based on the idea that a person focuses more on attributes in which her options differ more. I will also use the framework to develop novel, focus-based, theories of intertemporal choice and social preferences, as well as analyze the implications of focusing for product design, principal-agent relationships, and other economic questions. My second main agenda is to explore some implications for market outcomes, welfare, and policy of the possibility that consumers misperceive certain aspects of products. I will investigate the circumstances that facilitate the profitable deception of consumers; firms' incentives for ""innovating"" deceptive products, including novel financial products aimed at exploiting investors; how firms' ability to distinguish naive and sophisticated consumers affects the consequences of deception; whether learning on the part of consumers will help them to avoid making mistakes; and how regulators and other observers can detect consumer mistakes from market data. Two further projects apply the model of reference-dependent utility I have developed in earlier work to understand the pricing and advertising behavior of firms. I will also aim to disseminate some of my work, along with other cutting-edge research in psychology and economics, in a Journal of Economic Literature survey on ""Behavioral Contract Theory."""

1 275 448 €

Start date: 2012-11-01, End date: 2018-10-31

The global performing arts community is requiring innovative systems to: a) document, transmit and preserve the knowledge contained in choreographic-dramaturgic practices; b) assist artists with tools to facilitate their compositional processes, preferably on a collaborative basis. The existing digital archives of performing arts mostly function as conventional e-libraries, not allowing higher degrees of interactivity or active user intervention. They rarely contemplate accessible video annotation tools or provide relational querying functionalities based on artist-driven conceptual principles or idiosyncratic ontologies. This proposal endeavours to fill that gap and create a new paradigm for the documentation of performance composition. It aims at the analysis of artists’ unique conceptual structures, by combining the empirical insights of contemporary creators with research theories from Multimodal Communication and Digital Media studies. The challenge is to design a model for a web-based collaborative platform enabling both a robust representation of performance composition methods and novel visualization technologies to support it. This can be done by analysing recurring body movement patterns and by fostering online contributions of users (a.o. performers and researchers) to the multimodal annotations stored in the platform. To accomplish this goal, two subjacent components must be developed: 1. the production of a video annotation-tool to allow artists in rehearsal periods to take notes over video in real-time and share them via the collaborative platform; 2. the linguistic analysis of a corpus of invited artists’ multimodal materials as source for the extraction of indicative conceptual structures, which will guide the architectural logics and interface design of the collaborative platform software.The outputs of these two components will generate critical case-studies to help understanding the human mind when engaged in cultural production processes.

1 378 200 €

Start date: 2014-05-01, End date: 2019-04-30

Non-invasive Brain Machine Interfaces (BMI) bring great promise for neuro-rehabilitation and neuro-prosthesis, as well as for brain control of everyday devices and performance of simple tasks. Over the last 15 years the interest in BMIs has grown substantially, and a variety of interfaces have been developed. The field has been growing dramatically, and market studies reveal an estimated market size of $1.46 billion by 2020. However, non-invasive BMIs have failed to reach the impressive control seen by BMIs implanted in the brain. To date, they require considerable training to reach a moderate level of control, they are susceptible to noise and interference, do not generalize between people and devices, and performance does not show long-term consolidation. Results from our ERC-funded work uncovered a new paradigm that dramatically improves these issues. We propose to develop a prototype for a novel, standalone, non-invasive, noise-resistant BMI, based on an unexplored BMI learning paradigm. In this POC we will 1) refine the brain signal interface (decoder) to be automatically customizable to each individual and produces faster training, 2) implement our BMI technology into a portable hardware-based system, and 3) develop a virtual reality/gaming training platform that will increase learning, performance and consolidation of BMI control. In addition to these technical aims, we propose to explore commercial opportunities and societal benefits, in particular in the health sector. We will conduct market analysis and develop a business case for this product, while expanding industry contacts for production and commercialization. The work proposed in this PoC grant will permit, for the first time to our knowledge, the development of a portable, stand-alone, noise-resistant, and easy to learn BMI, applicable across a wide set of devices, which will bring a significant social impact in health, entertainment and other applications.

149 625 €

Start date: 2016-09-01, End date: 2018-02-28