Parkinson’s disease (PD) has a long prodromal phase, in which latent cerebral changes can manifest itself as prodromal symptoms, for example idiopathic REM-sleep behavioural disorder (RBD), hyposmia, and cognitive-affective symptoms (e.g. anxiety and depression). Increasing evidence suggests that the propagation of brain dysfunction in PD may take different routes, i.e. bottom-up (brainstem-to-cortex) or top-down (cortex-tobrainstem), and that it may affect focal versus diffuse brain systems. Here we aim to link these different neurobiological routes of PD propagation to distinct neurocomputational mechanisms of cognitive-affective dysfunction. We hypothesize that brainstem-to-cortex versus cortex-to-brainstem propagation routes are associated with deficits in distinct cognitive computations, as well as distinct genetic and prodromal clinical phenotypes. By leveraging computational model-based analyses of cognition, we will localize specific cognitive deficits to cerebral systems (brainstem or cortex, focal or diffuse). These data will be linked to multi-modal neuroimaging markers of propagation, epidemic spreading models of brain dysfunction, and genetic risk factors (polygenic risk scores, and separate groups of non-manifesting GBA and LRRK2 mutation carriers). We will take advantage of existing longitudinal cohorts (>220 idiopathic RBD patients, >100 non-manifesting GBA/LRRK2 mutation-carriers, >750 early PD patients), where multimodal imaging and genotyping is available. These data will be enriched by deep, online cognitive/affective phenotyping. This study will, for the first time, link inter-individual differences in neurodegeneration propagation to prodromal cognitive-affective and clinical phenotypes. This may help to further improve the predictive value of already recognized prodromal factors, and it may offer a mechanism-based approach to treatment in prodromal PD

Tanycytes are ependymoglial cells in the wall of the third ventricle that play a central role in the regulation of neuroendocrine hormone axes and metabolism. Depending on their location in the ventricular wall, tanycytes have different properties. Our preliminary work in mouse models shows that subtypes of tanycyte are innervated by different neurons. One group of these neurons produces kisspeptin, which is an essential factor in the control of puberty and fertility. Interestingly, the stimulation of different tanycyte subtypes by kisspeptin has differential effects on the hypothalamic-pituitary-gonadal axis and the oestrous cycle of animals. In the proposed project, we first want to characterise the molecular structure of the unusual synaptoid contacts between kisspeptin neurons and tanycytes. Based on this, we want to clarify whether the synaptoid connections between kisspeptin neurons and tanycytes depend on the sex, age and hormone status of the animals. We propose to investigate whether kisspeptin influences the morphology of tanycytes and what effects the tanycytic response to kisspeptin has on puberty, fertility and metabolism of the animals. Answering these questions will be made possible by the collaboration between the two applicants, the exchange of new methods to genetically manipulate tanycyte subtypes and advanced microscopic techniques. In this way, the project will elucidate a previously unknown mechanism of neuroglial interaction and contribute to the understanding of neuroendocrine regulation of puberty and fertility.

We have identified an emerging need at EU level for training of new generation of the top-level researchers and researchers-clinicians, who will be ready to implement creative solutions by merging chronobiology, integrative molecular physiology and metabolic disease research fields. Our goal is to build a sustained network of the leading researchers in the fields of integrative physiology, metabolism, lifestyle medicine. The setbacks in embracing the circadian biology concepts by different fields can be largely explained by the complexity of molecular clock mechanisms, rapidly developing methodology that often requires specific equipment and expertise, large dataset analyses and elaborate computational approaches to integrate cross-field data. Notably, there are only a few dedicated training programs in university curricula focusing on chronobiology and no EU-training networks for graduate students that would be devoted to circadian physiology. The PhysioTimeBridge training network responds to this need for basic researchers and clinicians with intersectoral and interdisciplinary expertise, who are fully trained to incorporate the time dimension in all the aspects of fundamental and clinical investigations in different fields of human physiology and specifically in translational studies of metabolic diseases. Our ambition is to introduce the knowledge of human circadian physiology to patient sample collection and analyses, and to promote preparation of the specialists ready to implement innovative personalized lifestyle medicine. Importantly, given the omnipresence of the circadian clock, the skills and knowledge acquired by trainees through PhysioTimeBridge network will be transferable to other fields such as immunity, cancer, aging etc. The complementary expertise of partners in the PhysioTimeBridge consortium in chronobiology, physiology of different organs and in variety of model systems will allow us to achieve the comprehensive training of early-stage researchers from cellular to animal models and translational studies from genetic mouse models to humans. We aim to design 10 collaborative PhD projects that will combine state-of-the art methodology in circadian physiology and lifestyle medicine. These will be intertwined with lecture courses and practical workshops on research and transferable skills provided by academic, clinical and industry background that will be engaged in the training network. The PhysioTimeBridge training program will embrace the three aims: 1) To TRAIN a new generation of PhD and MD-PhD through completion of research projects, secondments within the network, organization of lecture and practical school programs as well as local and network-wide trainings. 2) To LEARN by completing individual projects addressing research challenges of integrative chronobiology and physiology field: (i) to discover molecular mechanisms for metabolic chrono-alignment; (ii) to understand the molecular mechanisms of inter-organ circadian communication; (iii) to develop the basis for general application of lifestyle medicine. 3) To CREATE sustainable network of researchers that will embody a new school of the integrative physiology-chronobiology experts who are ready to challenges of academia, clinical and private sector. Altogether, the PhysioTimeBridge network has an ambition to place Europe at the forefront of research on chronobiology and lifestyle medicine contributing to its industrial leadership on health and shifting minds among the medical community, the patients and the policy makers.