Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a 15N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated 15N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.

SignificanceIngesta leave characteristic wear features on the tooth surface, which enable us to reconstruct the diet of extant and fossil vertebrates. However, whether dental wear is caused by internal (phytoliths) or external (mineral dust) silicate abrasives is controversially debated in paleoanthropology and biology. To assess this, we fed guinea pigs plant forages of increasing silica content (lucerne < grass < bamboo) without any external abrasives, both in fresh and dried state. Abrasiveness and enamel surface wear increased with higher forage phytolith content. Additionally, water loss altered plant material properties. Dental wear of fresh grass feeding was similar to lucerne browsing, while dried grass caused more grazer-like wear. Fresh grass grazing could be confounded with browsing, being a major pitfall for paleodietary reconstructions.

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Lepidosauria show a large diversity in dietary adaptations, both among extant and extinct tetrapods. Unlike mammals, Lepidosauria do not engage in sophisticated mastication of their food and most species have continuous tooth replacement, further reducing the wear of individual teeth. However, dietary tendency estimation of extinct lepidosaurs usually rely on tooth shape and body size, which allows only for broad distinction between faunivores and herbivores. Microscopic wear features on teeth have long been successfully applied to reconstruct the diet of mammals and allow for subtle discrimination of feeding strategies and food abrasiveness. Here, we present, to our knowledge, the first detailed analysis of dental microwear texture on extant lepidosaurs using a combination of 46 surface texture parameters to establish a framework for dietary tendency estimation of fossil reptilian taxa. We measured dental surface textures of 77 specimens, belonging to herbivorous, algaevorous, frugivorous, carnivorous, ovivorous, insectivorous, molluscivorous, as well as omnivorous species. Carnivores show low density and shallow depth of furrows, whereas frugivores are characterized by the highest density of furrows. Molluscivores show the deepest wear features and highest roughness, herbivores have lower surface roughness and shallower furrows compared to insectivores and omnivores, which overlap in all parameters. Our study shows that despite short food–tooth interaction, dental surface texture parameters enable discrimination of several feeding strategies in lepidosaurs. This result opens new research avenues to assess diet in a broad variety of extant and extinct non-mammalian taxa including dinosaurs and early synapsids.

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Food processing wears down teeth, thus affecting tooth functionality and evolutionary success. Other than intrinsic silica phytoliths, extrinsic mineral dust/grit adhering to plants causes tooth wear in mammalian herbivores. Dental microwear texture analysis (DMTA) is widely applied to infer diet from microscopic dental wear traces. The relationship between external abrasives and dental microwear texture (DMT) formation remains elusive. Feeding experiments with sheep have shown negligible effects of dust-laden grass and browse, suggesting that intrinsic properties of plants are more important. Here, we explore the effect of clay- to sand-sized mineral abrasives (quartz, volcanic ash, loess, kaolin) on DMT in a controlled feeding experiment with guinea pigs. By adding 1, 4, 5, or 8% mineral abrasives to a pelleted base diet, we test for the effect of particle size, shape, and amount on DMT. Wear by fine-grained quartz (>5/<50 µm), loess, and kaolin is not significantly different from the abrasive-free control diet. Fine silt-sized quartz (∼5 µm) results in higher surface anisotropy and lower roughness (polishing effect). Coarse-grained volcanic ash leads to significantly higher complexity, while fine sands (130 to 166 µm) result in significantly higher roughness. Complexity and roughness values exceed those from feeding experiments with guinea pigs who received plants with different phytolith content. Our results highlight that large (>95-µm) external silicate abrasives lead to distinct microscopic wear with higher roughness and complexity than caused by mineral abrasive-free herbivorous diets. Hence, high loads of mineral dust and grit in natural diets might be identified by DMTA, also in the fossil record.

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External abrasives ingested along with the herbivore diet are considered main contributors to dental wear, though how the different sizes and concentrations of these abrasives influence wear remains unclear. Dental microwear texture analysis (DMTA) is an established method for dietary reconstruction which describes a tooth's surface topography on a micrometre scale. The method has yielded conflicting results as to the effect of external abrasives. In the present study, a feeding experiment was performed on sheep (Ovis aries) fed seven diets of different abrasiveness. Our aim was to discern the individual effects of size (4, 50 and 130 µm) and concentration (0%, 4% and 8% of dry matter) of abrasives on dental wear, applying DMTA to four tooth positions. Microwear textures differed between individual teeth, but surprisingly, showed no gradient along the molar tooth row, and the strongest differentiation of experimental groups was achieved when combining data of all maxillary molars. Overall, a pattern of increasing height, volume and complexity of the tooth's microscopic surface appeared with increasing size of dietary abrasives, and when compared with the control, the small abrasive diets showed a polishing effect. The results indicate that the size of dietary abrasives is more important for dental microwear texture traces than their concentration, and that different sizes can have opposing effects on the dietary signal. The latter finding possibly explains conflicting evidence from previous experimental DMTA applications. Further exploration is required to understand whether and how microscopic traces created by abrasives translate quantitatively to tissue loss.