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Acclimatization to middle altitude hypoxia protects against developmental and cognitive deficits caused by acute fetal hypoxia in mice

LIU Hui-Lang, SUN Yong-Mei, LI Chuan-Yu, NIU Hai-Chen, SU Min, WANG Jing-Kun

Yunnan Institute of Materia Medica, Innovation and R&；D Center of Yunnan Baiyao Group Co., Ltd., Yunnan Province Company Key Laboratory for TCM and Ethnic Drug of New Drug Creation, Kunming 650111, China； Department of Molecular and Cellular Neurobiology, Center for Neurogenomics &； Cognitive Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, Netherlands； Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China； Department of Genetics, Xuzhou Medical University, Xuzhou 221004, China

Abstract

Acute fetal hypoxia (AFH) can elicit postnatal motor deficits and cognitive impairments. To test whether lifelong acclimatization to middle altitude (MA) hypoxia has protective effects on the impairments caused by AFH, ICR mice bred at 1 900 m altitude for 6–7 generations were evaluated under AFH. On gestation day 9 (GD 9), 13 (GD 13) or 17 (GD 17), pregnant mice received a single exposure to acute hypoxia (7% O2, 6 h). Physiological and neurodevelopmental behaviors, motor function (open field), spatial learning and memory (Morris water maze), and anxiety level (elevated plus maze) were examined in the offspring from neonate to adulthood. In the neonatal age, among all the physiological and behavioral landmarks, almost no differences were found in the hypoxia groups. In the juvenile period, no obvious impairments of motor function and anxiety level were found in the hypoxia groups. In the adult period, no obvious impairment of motor function was found in hypoxia groups; Interestingly, AFH groups’ offspring showed normal or enhanced long-term spatial memory ability after AFH. These data suggest that AFH cause little abnormalities in the offspring of MA-adapted mice. To further investigate the underlying mechanisms, the neuronal numbers in behavior-related brain areas (accumbens nucleus, basal amygdala and hippocampus) were counted, and the physiological parameters of the blood were measured. The morphological data showed that no obvious neuronal necrosis was found in all hypoxia groups. In addition, blood tests showed that red blood corpuscle count, hemoglobin concentration and hematocrit levels in mice raised at MA were markedly higher in both males and females, compared with controls raised at the sea level. These data suggest that lifelong acclimatization to MA hypoxia has protective effects against development delay, motor deficits and spatial learning and memory impairments induced by AFH, and the protective effects may be due to higher hemoglobin concentration and hematocrit levels in the blood. The findings may provide a better understanding of fetal hypoxia and potential intervention treatments.

Key words: hypoxia acclimatization; neuroprotective function ; acute fetal hypoxia ; developmental disorder ; cognitive disorder

Received: 2016-11-05　　Accepted: 2016-12-31

Corresponding author: 刘慧浪　　E-mail: liuhuilang@163.com

Citing This Article：

LIU Hui-Lang, SUN Yong-Mei, LI Chuan-Yu, NIU Hai-Chen, SU Min, WANG Jing-Kun. Acclimatization to middle altitude hypoxia protects against developmental and cognitive deficits caused by acute fetal hypoxia in mice. Acta Physiol Sin 2017; 69 (2): 146-158