ERC FUNDED PROJECTS

Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy. ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions. Relying on these approaches the main objectives of ALFA are thus to: - Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it; - Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences; - Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe. ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.

1 871 250 €

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

Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders

2 000 000 €

Start date: 2017-04-01, End date: 2022-03-31

Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets. We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits. Thus using a multidisciplinary approach we will investigate: 1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function 2) the activity-dependent dynamics of Cx30 function at synapses 3) a role for Cx30 in wiring synaptic circuits during critical developmental periods This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.

2 000 000 €

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

The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve: 1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance. 2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance. 3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects. This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.

1 997 748 €

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