title: Hippocampal UCP2 is essential for cognition and resistance to anxiety but not required for the benefits of exercise.
abstract: Uncoupling protein-2 (UCP2) reduces oxidative stress by facilitating the influx of protons into mitochondrial matrix, thus dissociating mitochondrial oxidation from ATP synthesis. UCP2 is expressed abundantly in brain areas and plays a key role in neuroprotection. Here, we sought to determine if UCP2 deficiency produces cognitive impairment and anxiety in young mice, and to determine if hippocampal UCP2 is essential for the beneficial effects of voluntary exercise. Antisense oligonucleotide (ASO) was used to produce UCP2 knockdown in mice. Our results firstly showed that UCP2-targeted ASO significantly reduced UCP2 mRNA and protein expression in the hippocampus. ASO treatment impaired learning and memory of the mice in Y-maze, T-maze, and object recognition tests (ORT). ASO-treated mice exhibited more anxiously in OPT, light/dark box test, and elevated plus maze (EPM) than the control mice. We also found that wheel running ameliorated cognitive dysfunction and anxiety-like behaviors in ASO-treated mice. Furthermore, voluntary exercise reversed ASO-induced changes in hippocampal levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE). However, UCP2 protein in the hippocampus was not correlated with cognitive and anxiolytic benefits of exercise. These findings suggest that hippocampal UCP2 is essential for cognitive function and the resistance to anxiety of mice, but not required for the beneficial effects of exercise.
authors.affiliation: College of Sports Medicine and Rehabilitation, Research Institute of Sports Medicine, Taishan Medical University, Tai'an, Shandong 271016, China. Electronic address: wangdm72@126.com.
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Traditional Chinese Medicine, Changhai Hospital, Shanghai 200438, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhai
authors.affiliation: College of Basal Medical Sciences, Taishan Medical University, Tai'an, Shandong 271016, China.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.affiliation: Institute of Atherosclerosis, Taishan Medical University, Tai'an, Shandong 271016, China.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: College of Biological Science, Taishan Medical University, Tai'an, Shandong 271016, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: College of Sports Medicine and Rehabilitation, Research Institute of Sports Medicine, Taishan Medical University, Tai'an, Shandong 271016, China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: College of Sports Medicine and Rehabilitation, Research Institute of Sports Medicine, Taishan Medical University, Tai'an, Shandong 271016, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000503:physiopathology / Q000628:therapy; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D005082:Physical Exertion / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D055500:Resilience, Psychological; D012420:Running / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D065852:Spatial Memory / Q000502:physiology; D000071246:Uncoupling Protein 2; D014836:Volition
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine
keywords: antisense oligonucleotide; anxiety; cognition; hippocampus; uncoupling protein-2; voluntary exercise