Five leading European supercomputing centres are committed to develop, within their respective national programs and service portfolios, a set of services that will be federated across a consortium. The work will be undertaken by the following supercomputing centres, which form the High Performance Analytics and Computing (HPAC) Platform of the Human Brain Project (HBP): ▪ Barcelona Supercomputing Centre (BSC) in Spain, ▪ The Italian supercomputing centre CINECA, ▪ The Swiss National Supercomputing Centre CSCS, ▪ The Jülich Supercomputing Centre in Germany, and ▪ Commissariat à l'énergie atomique et aux énergies alternatives (CEA), France (joining in April 2018). The new consortium will be called Fenix and it aims at providing scalable compute and data services in a federated manner. The neuroscience community is of particular interest in this context and the HBP represents a prioritised driver for the Fenix infrastructure design and implementation. The Interactive Computing E-Infrastructure for the HBP (ICEI) project will realise key elements of this Fenix infrastructure that are targeted to meet the needs of the neuroscience community. The participating sites plan for cloud-like services that are compatible with the work cultures of scientific computing and data science. Specifically, this entails developing interactive supercomputing capabilities on the available extreme computing and data systems. Key features of the ICEI infrastructure are: ▪ Scalable compute resources; ▪ A federated data infrastructure; and ▪ Interactive Compute Services providing access to the federated data infrastructure as well as elastic access to the scalable compute resources. The ICEI e-infrastructure will be realised through a coordinated procurement of equipment and R&D services. Furthermore, significant additional parts of the infrastructure and R&D services will be realised within the ICEI project through in-kind contributions from the participating supercomputing centres.

Brain disorders affect ~179 million people and their families in Europe alone, with an annual cost to the taxpayer estimated at €800 billion- a greater economic burden than cardiovascular disease and cancer combined. Despite diverse etiology, overlap in clinical symptoms and comorbidities between brain disorders suggests shared patho-mechanisms. In particular, hyperexcitible states driven by glial activation and neuroinflammation appear near ubiquitous. Targeting these mechanisms offers the potential to ameliorate symptoms and reverse disease progression across a broad span of brain disorders. Functioning as a gatekeeper to neuroinflammation and mechanistic link between neuronal hyperexcitability and glial activation, the ATP-gated, ionotropic purinergic P2X7 receptor (P2X7R) offers the most promising target for pharmacological intervention in the neuroinflammation-hyperexcitability pathway, to date. With breakthroughs in understanding P2X7R function, highly promising effects demonstrated for antagonists in models of brain disease and vast investment in P2X7R-related drug development programmes, now is the perfect time to pool resources. PurinesDX brings together global leaders in translational research in purinergic signalling, Europe’s leading clinical specialists in a broad range of brain diseases, and industrial partners specializing in drug and biomarker development. Sharing unique genetic tools, newly developed diagnostic devices and novel, selective and brain-stable P2X7R antagonists, the synergism facilitated within PurinesDX will extend to the training of an urgently needed new generation of highly skilled, innovative, creative and entrepreneurial scientists. Alongside the provision of this interdisciplinary, international and intersectoral environment, an original and high level training in state-of-the-art neuroscience will be provided, nurturing a cohort of highly competitive researchers with potential to drive a new era of neuroscience research.

Neurological diseases cause enormous suffering and a great economic burden. Almost 20 million Europeans are affected by the most frequently occurring and disabling disease entities, such as stroke, Alzheimer’s disease (AD), or multiple sclerosis (MS), and these numbers do not include the large group of rare diseases that affect the CNS. Overall, the annual costs for patient care amount to 400 billion Euros. Common features of many neurological diseases are a vascular pathology with impaired blood-brain barrier (BBB) function or with reduced blood flow and inflammatory changes. As the two are often associated, disentangling their intricate and mutual relationship is a major task for translational neuroscience that could improve the treatment of many neurological diseases. At the cellular level, key players are brain endothelial cells as the building blocks of cerebral vessels and macrophages as the main inflammatory cells of the brain. Recent discoveries indicate that endothelial cells and brain macrophages are in intimate contact and closely interact. However, there is a huge gap of knowledge regarding the specific mode and the consequences of these interactions. Therefore, in-depth analyses of the molecular mechanisms involved are essential to identify and understand key features of macrophage-endothelial cross-talk, and exploitation of this information for the development of treatments of neurological diseases. ENTRAIN will undertake this task, using novel and emerging technologies, such as cutting-edge chemoproteomics, unique genetic and viral tools for targeting of defined cell populations, and high resolution intravital imaging. By characterising the pas de deux of endothelial cells and macrophages at the functional and morphological level, we will lay the foundation for better therapies for neurological diseases. The results will impact on the understanding of neuroinflammation, but also on the rarefaction of vessels.

Parkinson’s disease is dominated by motor symptoms such as tremor, bradykinesia and postural instability. However, over 90% of all patients develop cognitive impairment including deterioration of learning, memory and decision making. Current treatments focus on motor symptoms and offer at best moderate improvement of cognitive functions. Alleviating cognitive symptoms could dramatically increase quality of life of patients. Therefore, we propose to apply a behavioral test of fine decision making combined with electroencephalography and electromyography measurements to quantitatively assess complex aspects of cognitive function, including inhibitory control, learning by reinforcement and decision making under conflict. This Quantitative Cognitive Testing (QCT) can be employed to improve Parkinson’s disease therapy based on regular feedback. Moreover, the method can be extended to other domains of neurodegenerative dementias. We foresee that the application of QCT can facilitate the development of telemedicine packages, thus reducing hospital visits and patient-doctor contacts. Under this PoC, we propose to validate equipment we developed de novo, conduct proof of concept experiments, extend IPR protection, and explore commercialization strategies. We believe that QCT can help achieve the best possible cognitive function, which would improve the quality of life of patients and their families. It could also reduce disease-related cost burden on health care systems and society, making it appealing to health providers.

Our astonishing cognitive abilities are the consequence of complex connectivity within our neuronal networks and the large functional diversity of excitable nerve cells and their synapses. Investigations over the past half a century revealed dramatic diversity in shape, size and functional properties among synapses established by distinct cell types in different brain regions and demonstrated that the functional differences are partly due to different molecular mechanisms. However, synaptic diversity is also observed among synapses established by molecularly and morphologically uniform presynaptic cells on molecularly and morphologically uniform postsynaptic cells. Our hypothesis is that quantitative molecular differences underlie the functional diversity of such synapses. We will focus on hippocampal CA1 pyramidal cell (PC) to mGluR1α+ O-LM cell synapses, which show remarkable functional and molecular heterogeneity. In vitro multiple cell patch-clamp recordings followed by quantal analysis will be performed to quantify well-defined biophysical properties of these synapses. The molecular composition of the functionally characterized single synapses will be determined following the development of a novel postembedding immunolocalization method. Correlations between the molecular content and functional properties will be established and genetic up- and downregulation of individual synaptic proteins will be conducted to reveal causal relationships. Finally, correlations of the activity history and the functional properties of the synapses will be established by performing in vivo two-photon Ca2+ imaging in head-fixed behaving animals followed by in vitro functional characterization of their synapses. Our results will reveal quantitative molecular fingerprints of functional properties, allowing us to render dynamic behaviour to billions of synapses when the connectome of the hippocampal circuit is created using array tomography.