ERC FUNDED PROJECTS

Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis. We propose to: 1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour. 2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid. This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.

2 439 996 €

Start date: 2011-04-01, End date: 2017-03-31

A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.

1 284 808 €

Start date: 2010-02-01, End date: 2015-01-31

Recent technological advances in optical microscopy have vastly broadened the possibilities for applications in the biomedical sciences. Fluorescence microscopy is the central tool for investigation of molecular structures and dynamics that take place in the cellular and tissue environment. Coupled with progress in labeling methods, these microscopes permit observation of biological structures and processes with unprecedented sensitivity and resolution. This work has been enabled by the engineering development of diverse optical systems that provide different capabilities for the imaging toolkit. All such methods rely upon high fidelity optics to provide optimal resolution and efficiency, but they all suffer from aberrations caused by refractive index variations within the specimen. It is widely accepted that in many applications this fundamental problem prevents optimum operation and limits capability. Adaptive optics (AO) has been introduced to overcome these limitations by correcting aberrations and a range of demonstrations has shown clearly its potential. Indeed, it shows great promise to improve virtually all types of research or commercial microscopes, but significant challenges must still be met before AO can be widely implemented in routine imaging. Current advances are being made through development of bespoke AO solutions to individual imaging tasks. However, the diversity of microscopy methods means that individual solutions are often not translatable to other systems. This proposal is directed towards the creation of theoretical and practical frameworks that tie together AO concepts and provide a suite of scientific tools with broad application. This will be achieved through a systems approach that encompasses theoretical modelling, optical engineering and the requirements of biological applications. Additional outputs will include practical designs, operating protocols and software algorithms that will support next generation AO microscope systems.

3 234 789 €

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

The objective of this proposal is to bring together a local team of young researchers who will work closely with international collaborators to advance the state of the art of Algorithmic Game Theory and open new venues of research at the interface of Computer Science, Game Theory, and Economics. The proposal consists mainly of three intertwined research strands: algorithmic mechanism design, price of anarchy, and online algorithms. Specifically, we will attempt to resolve some outstanding open problems in algorithmic mechanism design: characterizing the incentive compatible mechanisms for important domains, such as the domain of combinatorial auctions, and resolving the approximation ratio of mechanisms for scheduling unrelated machines. More generally, we will study centralized and distributed algorithms whose inputs are controlled by selfish agents that are interested in the outcome of the computation. We will investigate new notions of mechanisms with strong truthfulness and limited susceptibility to externalities that can facilitate modular design of mechanisms of complex domains. We will expand the current research on the price of anarchy to time-dependent games where the players can select not only how to act but also when to act. We also plan to resolve outstanding questions on the price of stability and to build a robust approach to these questions, similar to smooth analysis. For repeated games, we will investigate convergence of simple strategies (e.g., fictitious play), online fairness, and strategic considerations (e.g., metagames). More generally, our aim is to find a productive formulation of playing unknown games by drawing on the fields of online algorithms and machine learning.

2 461 000 €

Start date: 2013-04-01, End date: 2019-03-31