Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Singlecell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks-challenged by cognitive tasks-drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression. 1 1234567890():,;E rythropoietin (EPO) is a hypoxia-inducible growth factor in mammalian kidney, named after its role in hematopoiesis 1,2 . Unexpectedly, both EPO and its receptor (EPOR) were later detected in the brain, where they are upregulated by injury conditions. High-dose recombinant human (rh) EPO, a drug in clinical use for anemic patients, exerts neuroprotective and neuroregenerative effects that are independent of the hematocrit, which is mechanistically unexplained 3-8 . Moreover, rhEPO improves cognitive function and reduces gray matter loss in a range of neuropsychiatric conditions 9-13 . Even in healthy mice, rhEPO treatment improves cognition, which is associated with enhanced hippocampal long-term potentiation [14][15][16] . Surprisingly, rhEPO increases the number of mature hippocampal pyramidal neurons without underlying effect on cell proliferation or cell death 17 . This effect is mediated in neurons mainly by JAK-STAT, PI3K/AKT/PKB, Ras-MEK, and ERK1/2, as well as NF-κB; pathways widely comparable to the hematopoietic system [18][19][20] . This raises the question whether the expression of EPO and its receptor serves a physiological function in the nervous system, and what could be the triggering factors of EPO expression under physiological conditions. ResultsGeneration of pyramidal neurons in adult mice and amplification by rhEPO. First, we developed a method to directly label and quantify newly generated neurons in the hippocampal cornu ammonis (CA) field of adult mice. This was possible by permanently labeling all mature pyramidal neurons present at P27 using a tamoxifen-inducible reporter gene in NexCreERT2::R26R-tdT mice (Fig. 1a, b) 21 . Thus, all neurons differentiating and maturing after termination of the tamoxifen-induced Cre recombination lack tdTomato, but can be positively identified by Ctip2, a specific marker of pyramidal neurons, thereby revealing adult 'neurogenesis' independent of DNA synt...

The prevalence of Alzheimer's disease (AD), the leading cause of dementia, shows a strict age-dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter associated with secondary neuroinflammation. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing-associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the primary neuropathological hallmark of AD. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia but show a disease-associated microglia (DAM)-like signature as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. Our data suggest a working model, in which age-dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.

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. Here we show 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, allows 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 report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest 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.

Highlights d Microglia transiently respond to EPO by apoptosis, followed by abridged proliferation d Reduction of microglia allows undisturbed fast differentiation of immature neurons d Microglial and pyramidal EPOR are critical for neurodifferentiation in CA1 on EPO d EPO acts as regulator of neuronally expressed IL-34 and CSF1R-dependent microglia