ERC FUNDED PROJECTS

Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).

2 499 947 €

Start date: 2010-04-01, End date: 2016-03-31

Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.

2 076 126 €

Start date: 2010-04-01, End date: 2015-03-31

Crustal magmatism is periodic on a very wide range of timescales from pulses of continental crustal growth, through formation of granite batholiths, to eruptions from individual volcanic centres. The cause of this periodicity is not understood. I aim to address this long-standing geological problem through a combination of experiments, petrological methods and numerical models via a novel proposal that periodicity arises because of the highly non-linear ( critical ) behaviour of magma crystallinity with temperature in a series of linked crustal magma reservoirs. The ultimate objective is to answer five fundamental questions: " Why is crustal magmatism episodic? " How are large batholiths formed of rather similar magmas over long periods of time? " How do large bodies of eruptible magma develop that can lead to huge, caldera-forming eruptions? " What controls the chemistry of crustal magmas? Why are some compositions over-represented relative to others? " What is the thermal structure beneath volcanic arcs and how does it evolve with time? The project will address these questions through case studies of three contrasted active volcanoes: Nevado de Toluca, Mexico; Soufriere St Vincent, Lesser Antilles; and Mount Pinatubo, Philippines. For each volcano I will use experimental petrology to constrain the phase relations of the most recently erupted magma as a function of pressure, temperature, volatile content and oxygen fugacity in the shallow, sub-volcanic storage region. I will also carry out high-pressure phase equilibria on coeval Mg-rich basaltic rocks from each area with the aim of constraining the lower crustal conditions under which the shallow magmas were generated and use diffusion chronometry to constrain the frequency of magmatic pulses in the sub-volcanic reservoirs. The project will result in a quantum leap forwards in how experimental and observational petrology can be used to understand magmatic behaviour beneath hazardous volcanoes

2 959 518 €

Start date: 2010-04-01, End date: 2015-03-31

What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.

2 416 078 €

Start date: 2010-06-01, End date: 2016-05-31