Hypoxia is the term for reduced oxygenation of cells and tissues. Earlier interpreted as principally pathological, e.g. upon cardiac arrest, hypoxia is increasingly recognized as a strong driver of development including angiogenesis, hematopoiesis, or regeneration. In 2019, P.J. Ratcliffe, together with W.G. Kaelin & G.L. Semenza, received the Nobel Prize in Physiology and Medicine for their ground-breaking discoveries of how cells sense and adapt to oxygen availability. These fundamental discoveries are currently systematically translated to normal brain functions, where hypoxia likely has a central, yet unheralded role. This LEOPOLDINA Symposium on the role of physiological hypoxia for treating brain disorders will step in exactly this direction and extend to highly innovative, potential future treatment concepts.
The symposium will start with a Nobel Lecture of Sir Peter J. Ratcliffe, Oxford, who will give an overview of his pivotal work on oxygen sensing and hypoxia signaling pathways. On these crucial grounds, the other speakers will build their presentations. Max Gassmann, Zürich will talk on hypobaric hypoxia as achieved at high altitude and report on its potential benefits as well as mediating mechanisms. Peter Falkai, München, will show how exercise can act as driving force for cognition and neuroplasticity in humans, leading to improved global brain dimensions and function, including mood. Finally, Hannelore Ehrenreich, Göttingen, will provide mechanistic insight and show in translational approaches that neurons respond to motor-cognitive challenge with 'functional hypoxia' mediating brain hardware upgrade.
15:30 Uhr
Nobel Lecture – Oxygen sensing and hypoxia signaling pathways
P. Ratcliffe (Oxford, GB)
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P. Ratcliffe (Oxford, GB)
Maintenance of oxygen homeostasis is a fundamental physiological challenge, whilst low oxygen (hypoxia) is an important component of most human diseases. Work which commenced with studies of the oxygen-regulated expression of the erythropoietin gene in the kidneys and liver led to the discovery of a widespread system of oxygen sensing and transcriptional control which operates in essentially all animal cells. This pathway transduces a broad range of cellular and systemic responses to hypoxia, including the regulation of energy metabolism, angiogenesis, erythropoiesis and cell differentiation and survival decisions.
The oxygen sensitive signal is generated by a set of oxygen splitting enzymes, which catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in the transcription factor hypoxia inducible factor (HIF). HIF prolyl hydroxylation targets HIF-alpha polypeptides for destruction by the von Hippel-Lindau (pVHL) ubiquitin E3 ligase, whilst HIF asparaginyl hydroxylation inhibits co-activator recruitment and reduces transcriptional activation. In hypoxia these processes are suppressed, allowing HIF-alpha to escapade destruction and form an active transcriptional complex.
Although the use of post-translational hydroxylation in the regulation of HIF was unprecedented as a signalling mechanism, it is now known that all four eukaryotic kingdoms deploy different types of enzymatically catalysed protein oxidation linked to protein degradation to signal oxygen levels. Plants deploy enzyme-catalysed cysteine dioxygenation coupled to the N-degron pathway. Recent work has shown that this pathway also operates in human cells alongside the HIF hydroxylase pathway, but interacts directly with the regulation of G-protein signals in specific cells.
The lecture will describe the discovery of these pathways and compare and contrast their physiology.
15:52 Uhr
What high altitude research teaches us regarding benefits of inspiratory hypoxia
M. Gassmann (Zürich, CH)
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M. Gassmann (Zürich, CH)
About 7% of the world’s population lives above 1500 m above sea level (masl) and as a consequence, the hemoglobin (Hb) levels increases. It remains unclear whether moderate altitude (where most people live at) alters erythropoiesis. Such information is required to accurately define Hb thresholds to diagnose anemia and polycythemia in populations living at moderate altitude. We evaluated Hb, ferritin levels, and C-reactive protein (CRP) levels in relation to the residential altitude of 71,798 Swiss men aged 18-22 years. The anonymized individual conscription data (covering >90% of Swiss male birth cohorts) were collected by the Swiss Army. Blood samples from volunteers were always analyzed within 12 hours by one single certified Swiss laboratory. Notably, Hb levels significantly increased for every 300 meters of increased residential altitude. Average Hb values increased by a maximum of 2.84% from conscripts living between about 300 and 1800 masl. Plasma ferritin levelssignificantly increased with altitude independently of the Hb, demonstrating for the first time that iron stores are subject to control by moderate altitude increases. Moderate altitude must be considered when interpreting Hb and iron levels for a given population even when residing at altitudes below 1500 masl. The adjustment of Hb levels even at moderate altitude allowed to draw a topographical map of Switzerland and suggests a high precision oxygen-sensing mechanism, that most probably also applies for increasing iron stores in response to elevated altitude.
The question arises as why evolution has come up with such a precise oxygen sensing system. I speculate that oxygen sensing was not first develop to ultimately increase Hb levels but to protect other organs, especially the neuronal system, from reduced oxygen supply. As such, it might well be that oxygen-dependent erythropoietin expression was originally developed to exert a neuroprotective function that is still found in mammals.
16:14 Uhr
Exercise as a driving force for cognition and neuroplasticity in humans
P. Falkai (München, DE)
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P. Falkai (München, DE)
Schizophrenia is a severe brain disorder characterised by positive, negative, affective and cognitive symptoms and can be regarded as a disorder of impaired neural plasticity. This lecture focusses on the beneficial role of exercise in schizophrenia and its underlying mechanisms.
Apart from the established pharmacological treatments in schizophrenia, aerobic exercise has a profound impact on the plasticity of the brain of both rodents and humans such as inducing the proliferation and differentiation of neural progenitor cells of the hippocampus in mice and rats. Aerobic exercise enhances LTP and leads to a better performance in hippocampus related memory tasks, eventually by increasing metabolic and synaptic plasticity related proteins in the hippocampus. In healthy humans, regular aerobic exercise increases hippocampal volume and seems to diminish processes of ageing like brain atrophy and cognitive decline.
Several meta-analyses demonstrate the beneficial effect of exercise on function, positive as well as negative symptoms and brain structure in multi-episode schizophrenia.
16:36 Uhr
Neurons respond to motor-cognitive challenge with functional hypoxia mediating brain hardware upgrade
H. Ehrenreich (Göttingen, DE)
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H. Ehrenreich (Göttingen, DE)
Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. We showed in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allowed us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control.
We found that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggested an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells. This intriguing model of neuroplasticity constitutes an essential part of what we coined the brain EPO circle, our working model explaining adaptive 'brain hardware upgrade' and improved performance. In this fundamental regulatory circle, neuronal networks, challenged by motor-cognitive tasks, drift into 'functional hypoxia', thereby triggering neuronal EPO expression. EPO substantially increases numbers of mature pyramidal neurons and oligodendrocytes in cornu ammonis hippocampi and reduces microglia and their activity/metabolism as prerequisites for undisturbed EPO-driven differentiation of pre-existing local neuronal precursors.