Chronic Exposure to Hypoxia Inhibits Myelinogenesis and Causes Motor Coordination Deficits in Adult Mice.

Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults, but the underlying mechanisms remain largely unknown. Since active myelinogenesis persists in the adult central nervous system, here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice. Using a transgenic approach to label newly-generated myelin sheaths (NG2-CreERTM; Tau-mGFP), we found that myelinogenesis was highly active in most brain regions, such as the motor cortex and corpus callosum. After exposure to hypoxia (10% oxygen) 12 h per day for 4 weeks, myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test. To determine the relationship between the inhibited myelination and functional impairment, we induced oligodendroglia-specific deletion of the transcription factor Olig2 by tamoxifen (NG2-CreERTM; Tau-mGFP; Olig2 fl/fl) in adult mice to mimic the decreased myelinogenesis caused by hypoxia. The deletion of Olig2 inhibited myelinogenesis and consequently impaired motor coordination, suggesting that myelinogenesis is required for motor function in adult mice. To understand whether enhancing myelination could protect brain functions against hypoxia, we treated hypoxic mice with the myelination-enhancing drug-clemastine, which resulted in enhanced myelogenesis and improved motor coordination. Taken together, our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.

Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia.

To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.

[Heavy metal pollution in street dusts from different functional zones of Luoyang City and its potential ecological risk].

The concentrations of heavy metals (Cu, Zn, Pb, Cr, Cd) in street dusts were investigated in six different functional zones of Luoyang City, i.e., urban-rural continuum, urban artery, industrial district, urban green space, residential district, and business district. The pollution levels and potential ecological risk of heavy metals were assessed by the methods of potential ecological risk index suggested by Håkanson. The results showed that heavy metal concentrations in street dusts from different functional zones of Luoyang City were all higher than soil background values in Henan, with average concentrations of Zn (1019.75 mg x kg(-1)) > Cr (401.63 mg x kg(-1)) > Cu (240.94 mg x kg(-1)) > Pb (176.04 mg x kg(-1)) > Cd (2.33 mg x kg(-1)). Cd was the most seriously polluted metal in all functional zones, and the average pollution index (Cf(i)) reached 35.84, following by Zn (16.32) > Cu (12.05) > Pb (7.90) > Cr (6.36). Heavy metal concentrations and pollution levels varied greatly in different functional zones, and industrial zone had the highest total contents and the heaviest pollution. The integrated potential ecological risk index (RI) in different functional zones all reached very strong levels, with an order of industrial district (1709.51) > urban green space (1581.50) > business district (1 297.45) > residential district (1 111.25) > urban artery (889.97) > urban-rural continuum (641.39). Among the surveyed heavy metals, Cd accounted for the major potential ecological risk, and the average potential ecological risk index (Er(i)) reached 1075.16 (extremely strong risk level) in all six functional zones. The average Er(i) of Cu and Pb reached 60.23 and 40.77 respectively, belonging to moderate risk level, while Zn (16.32) and Cr (12.71) only reached slight risk level. A reduction in industrial and traffic pollution might be the key measure to decrease the heavy metal pollution and potential risk in street dusts.