Myelinated axons propagate action potentials across otherwise unsurmountable distances. The overarching hypothesis of the cryoNERVE project is that membrane morphology crucially determines axonal health and function. Mutations in genes coding for membrane-shaping proteins are the major cause of familial axonopathies like hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth (CMT) disease. However, current techniques lack the resolution to ascertain the functions of these proteins and their pathological dysfunction within native nerves. At the same time, the highly specialized architecture of axons and their delicate interplay with glia can only be studied in situ. I have shown how cryo-electron tomography (cryo-ET) reveals the structural basis of neuronal function and disease within intact cells. However, cryo-ET imaging of tissues remains a major challenge. In cryoNERVE, we will develop cryo-ET workflows to image native nerve tissue at unprecedented resolution. We will build on these advances to study the function of HSP and CMT proteins within truly physiological environments. Specifically, we will investigate (i) how these proteins shape axonal organelles and their cross-talk, (ii) the mechanisms allowing myelin sheath formation and neuron-glia communication, and (iii) the alterations introduced by axonopathy-causing mutants. Lastly, we will pioneer the first cryo-ET analyses of vitrified human tissues. Frustratingly, peripheral nerve biopsies from axonopathy patients often cannot be diagnosed with existing methods. We will examine patient biopsies at molecular resolution, and capitalize on our findings in flies and mice to reveal hitherto obscured pathological abnormalities. Thus, cryoNERVE will provide a holistic molecular and structural basis of human axonopathies like HSP and CMT, pave the way for high-resolution analyses of native human tissues and explore the potential of cryo-ET as a diagnostic tool with nanometric precision.

Technological advancements in reproductive medicine have introduced the new concept of "FREEZING". Nowadays, healthy women are given the possibility to cryopreserve their oocytes in order to prolong their fertility, a procedure known as "social egg freezing". There is an ongoing bioethical academic and public debate on the social and ethical implications of this practice. The here proposed socio-empirical research is interested in extending our understanding of the concept of "freezing" in broader contexts, while analyzing it through the prism of 'sociology of time'. Egg freezing constitutes an extremely fascinating paradigm for studying concepts of time, timing, planning and its social-technological manipulation related to modern life science. In line with the IF work program's focus on creativity, innovation and diversity, this research aims to examine the interplay of culture and bioethics in an interdisciplinary and empirical manner, focusing on and comparing experts' and lay positions and using a cross-cultural German-Israeli comparative research framework. This cross-cultural comparison is especially interesting since the German regulatory and legal framework regarding new reproductive technologies is rather restrictive, while the Israeli regulation has been identified as extremely permissive. Using qualitative in depth interviews with relevant experts as well as users of social egg freeing, this research aims at (a) In-depth empirical analysis of time in the context of reproductive medicine; (b) A cross sectional analysis of social egg freezing by comparing two national contexts as well as experts and ordinary (lay) ethics; and (c) Theorization of the time dimension for the relationship of reproduction, labor and gender. Thus, this innovative research is expected to enhance the researcher academic competence and the transfer of new knowledge.

The TOPIC of this proposal is how a T-cell-driven autoimmune process can transform the brain into a chronically inflamed tissue afflicted by progressive neurodegeneration. The brain is considered to be an immune-privileged organ because immune cells have restricted access to its tissue and its resident cells can only exert limited immune functions. However, in the course of multiple sclerosis, a T-cell-induced chronic autoimmune disease of the brain, such aspects change dramatically and the brain tissue is transformed into an immunoactive milieu. These changes go hand in hand with a gradual degeneration of the neuronal tissue. What steers this transformative process in the brain is not yet understood. We have developed new experimental models and tools that enable us to follow and functionally test this transition from healthy into degenerating brain tissue in real time. We found that autoaggressive T cells within autoimmune lesions were frequently in direct contact with neurons or were partially or even completely inside the cytoplasm of neurons. Repeated T-cell-mediated autoimmune attacks of the CNS grey matter induce persistent inflammatory lesions with proceeding neurodegeneration. This leads us to the HYPOTHESIS that T cells not only trigger the initiation of autoimmune disease bouts but in addition directly contribute to the chronification of the disease by irreversibly shifting brain resident cells to an inflammatory program. The central AIM of this project is to uncover the mechanisms behind this T-cell-induced neuronal transformation process, particularly the functional consequences of the T-cell invasive behavior. Our VISION is to shed new light on this previously unknown function of autoaggressive T cells within the CNS tissue and thereby pave the way for new and targeted strategies to prevent autoimmunity-driven degeneration of the central nervous system.

Animals often interact in groups. Animal groups constitute complex sensory environments which challenge the brain and engage complex neural computations. This behavioral context is therefore fruitful for understanding how sophisticated neural computations give rise to behavior. However, it is also technically difficult since many of the relevant sensory cues arise from the members of the group and are therefore hard to quantify or control. Consequently, we only incompletely understand how the brain drives complex social behaviors in naturalistic contexts. To uncover the neural computations underlying social behavior in groups, we are using Drosophila, which provides unprecedented experimental access to the nervous system via genetic tools. Drosophila gathers on rotten fruit to feed and mate. Courtship and aggression dominate social interactions and rely on the recognition of sex-specific chemical cues and the production of context-specific acoustic signals. How are these multi-modal cues integrated to control and switch between courtship and aggression? How is unstable and conflicting sensory information resolved to promote stable behavioral strategies? How does sensory processing adapt to socially crowded environments in order to efficiently target behavior at individual members of the group? These issues will be addressed by combining computational modeling and genetic tools. Using machine learning, we will quantify and model the fine structure of social interactions to identify the social cues that drive behavior. Closed-loop optogenetics and calcium imaging in behaving animals will allow us to test the models and to ultimately reveal how the brain integrates, selects and combines social cues to drive social interactions. This multi-disciplinary approach will uncover the computational principles and mechanisms by which sensory information is processed to drive behavior in the complex sensory environment of animal groups.