Stress is the foremost consequence of human life and became a pressing societal burden through the many sensory and societal pressures that have evolved during the past decades. Severe stress induces maladaptive changes in the brain that clinically manifest as post-traumatic stress disorder (PTSD). Despite ~4% of the population presenting PTSD, only symptomatic therapies are available. In the ’SECRET-CELLS’ ERC award, we have identified a multimodal neurocircuit that induces brain-wide sensitization to stress through the sequential recruitment of hypothalamic, midbrain and then cortical neuronal circuits. Particularly, we identified protein targets that can simultaneously affect hormone and neurotransmitter release within this circuit and whose knock-out makes mice stress resilient. Therefore, we used unbiased proteomics to select protein interactors that participate in the related signaling cascades, determined the biochemical parameters of any such interaction and the X-ray structures of the relevant protein complexes. Moreso, a high-throughput screen was established to identify inhibitors. Here, we will apply this knowledge to use interacting proteins as templates for small-molecule inhibitor discovery and hit optimization. Subsequently, we will profile the pharmacology and cytotoxicity of the candidates in vitro. Thus, we will take critical steps towards developing a ‘circuit breaker’ that can inactivate the neuronal contingents that are causal to the development of PTSD. Thereby, we will offer a fundamentally novel framework for pharmacotherapy.

Immunoglobulins (Igs) are thought to influence formation of the microbiota composition during a critical window of opportunity in early life. Yet, the antigen binding profiles of these Igs are vastly unknown, and it is incompletely understood how early misguided immune education contributes to the development of allergies or asthma. On an even more fundamental level, it is also unclear if or how B cell receptor (BCR) sequences of different individuals converge to binding similar microbiota antigens and how such responses form in early life. Here, we will leverage phage display as well as novel approaches to study BCR sequence/Ig function relationships, focusing on the following objectives & research questions: a) How do immune exposures in early life shape Ig repertoires and influence health later on? We hypothesize that Ig repertoire development depends on the birth mode, duration of breast feeding, & antibiotics treatments. Here, we will deeply profile the Ig repertoires of mother-child dyads against 600,000 rationally selected microbiota antigens. We will also study the immune repertoires of children with allergies and mine these data sets for associations with early life Ig data sets. b) Do BCR sequences of different individuals converge to binding similar antigens? As observed for some viral antigens, we hypothesize that also universal responses towards bacterial antigens exist and we can capture such sequences in early life. We will apply state of the art and novel proprietary methodologies to link BCR sequences with Ig binding in adults & infants. Linking BCR sequence information with the actual antigen targets, will contribute to understanding the sequence-function relationship of Ig binding and their formation in early life. Deep profiling of mother-child dyads will provide new insights to the development of Ig repertoires. By comparing these datasets with allergic children may also reveal links between early immune education & lasting impacts on health.

Endeavours towards a more profound understanding of the neural architecture enabling the staggering cognitive abilities of the human brain hold high promises regarding diagnosis and treatment of various diseases affecting the neural system. The novel paradigm of brain connectomics has opened a wealth of insights into the individual differences, emergence, development, plasticity and disease specific re-organization of macro-scale brain networks composed by interconnected and synchronously operating neural units. Fetal neuroimaging, and in particular fetal magnetic resonance imaging (MRI) provides increasingly rich insights into the rapid prenatal neurodevelopment shaping the human connectome and establishing its capability to enable cognition or adapt and re-organize during disease. However, the exploration and study of this complex, highly multi-dimensional connectivity architecture, and its rapid change during gestation is still hampered by several limitations. PRECONFIG aims to overcome these limitations by developing novel techniques for the reliable and accurate capturing of structural and functional MRI brain connectivity in utero and integrating them into a quantitative model providing a complex feature-set that characterizes the developing fetal connectome ("fetal connectome fingerprint"). Ultimately, the project will deliver a canonical reference model, and algorithm implementation for artefact removal, brain network development modelling and detailed characterization of developmental disorders based on fetal MRI. Additionally it will provide a standard basis for reproducible and comparable research targeting the fetal connectome. Based on this, it will provide a proof-of-concept on the expediency of computational statistics and machine learning based stratification and prediction for clinical use of fetal MRI.

Continuing development of novel brain treatments, which bypass blood-brain barrier, further emerges the need to establish prognostic magnetic resonance (MR) markers to track progressive brain alteration in lysosomal storage diseases (LSD). Excessive intracellular accumulation of lysosomal substances such as glycosaminoglycans in mucopolysaccharidosis (MPS), globotriaosylceramide in Fabry disease and glycocerebroside in Gaucher disease (GD) triggers multi-organ malfunctioning and significant damage to the central nervous system. While LSD are associated with various levels of cognitive deficits, and distinct extents of morphological brain abnormalities (e.g., atrophy, leukodystrophy or enlarged perivascular spaces) ranging from non-existing in GD type 1 to severe in MPS type 2, microstructural and metabolic processes have not been comprehensively described in brains of LSD patients in vivo yet. We will utilize cutting-edge accelerated proton MR spectroscopic imaging methodology that was developed at the Medical University of Vienna in combination with advanced diffusion MRI, high-resolution T1-/T2-weighted ratio, and pseudo-continuous arterial spin labeling technique. Our protocol will reliably quantify levels of all relevant brain metabolites, while sensitively describe microstructural and functional deficits to determine the relevance of MR measures in psychological deficits in LSD. Reproducible MR methods are needed to assess effects of novel treatments that overcome blood-brain barrier such as intrathecal enzyme administration, chaperones and gene therapies in clinical LSD trials. Increased understanding of brain LSD pathology will critically boost search of optimal therapies in age-related neurodegenerative diseases that share some common features with LSD such as Alzheimer’s or Parkinson’s disease.