title: Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats.
abstract: Exposure to hypobaric hypoxia causes neuron cell damage, resulting in impaired cognitive function. Effective interventions to antagonize hypobaric hypoxia-induced memory impairment are in urgent need. Ketogenic diet (KD) has been successfully used to treat drug-resistant epilepsy and improves cognitive behaviors in epilepsy patients and other pathophysiological animal models. In the present study, we aimed to explore the potential beneficial effects of a KD on memory impairment caused by hypobaric hypoxia and the underlying possible mechanisms. We showed that the KD recipe used was ketogenic and increased plasma levels of ketone bodies, especially β-hydroxybutyrate. The results of the behavior tests showed that the KD did not affect general locomotor activity but obviously promoted spatial learning. Moreover, the KD significantly improved the spatial memory impairment caused by hypobaric hypoxia (simulated altitude of 6000 m, 24 h). In addition, the improving-effect of KD was mimicked by intraperitoneal injection of BHB. The western blot and immunohistochemistry results showed that KD treatment not only increased the acetylated levels of histone H3 and histone H4 compared to that of the control group but also antagonized the decrease in the acetylated histone H3 and H4 when exposed to hypobaric hypoxia. Furthermore, KD-hypoxia treatment also promoted PKA/CREB activation and BDNF protein expression compared to the effects of hypoxia alone. These results demonstrated that KD is a promising strategy to improve spatial memory impairment caused by hypobaric hypoxia, in which increased modification of histone acetylation plays an important role.
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Liying
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.
authors.forename: Kuiwu
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China.|Beijing Institute for Brain Disorders, 10 Xitoutiao, You Anmen, Fengtai District, Beijing, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, P.R.China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China.
authors.forename: Lingling
authors.identifier: http://orcid.org/0000-0002-6474-5875
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000107:Acetylation; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D055423:Diet, Ketogenic; D006657:Histones / Q000378:metabolism; D007657:Ketone Bodies / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000097:blood / Q000178:diet therapy* / Q000523:psychology; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D065852:Spatial Memory
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones; D007657:Ketone Bodies; D008055:Lipids; D017868:Cyclic AMP-Dependent Protein Kinases