title: Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction.
abstract: Chronic stress has a detrimental effect on neurological insults, psychiatric deficits, and cognitive impairment. In the current study, chronic stress was shown to impair learning and memory functions, in addition to reducing in hippocampal Adenosine monophosphate-activated protein kinase (AMPK) activity. Similar reductions were also observed for brain-derived neurotrophic factor (BDNF), synaptophysin, and post-synaptic density-95 (PSD-95) levels, all of which was counter-regulated by a regime of regular and prolonged exercise. A 21-day restraint stress regimen (6 h/day) produced learning and memory deficits, including reduced alternation in the Y-maze and decreased memory retention in the water maze test. These effects were reversed post-administration by a 3-week regime of treadmill running (19 m/min, 1 h/day, 6 days/week). In hippocampal primary culture, phosphorylated-AMPK (phospho-AMPK) and BDNF levels were enhanced in a dose-dependent manner by 5-amimoimidazole-4-carboxamide riboside (AICAR) treatment, and AICAR-treated increase was blocked by Compound C. A 7-day period of AICAR intraperitoneal injections enhanced alternation in the Y-maze test and reduced escape latency in water maze test, along with enhanced phospho-AMPK and BDNF levels in the hippocampus. The intraperitoneal injection of Compound C every 4 days during exercise intervention diminished exercise-induced enhancement of memory improvement during the water maze test in chronically stressed mice. Also, chronic stress reduced hippocampal neurogenesis (lower Ki-67- and doublecortin-positive cells) and mRNA levels of BDNF, synaptophysin, and PSD-95. Our results suggest that regular and prolonged exercise can alleviate chronic stress-induced hippocampal-dependent memory deficits. Hippocampal AMPK-engaged BDNF induction is at least in part required for exercise-induced protection against chronic stress.
authors.affiliation: Department of Society of Sports & Leisure Studies, Wonkwang University, 460 Iksandea-ro, Iksan, Jeonbuk, Republic of Korea.
authors.forename: D-M
authors.initials: DM
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and TIDRC, School of Medicine, Ewha Women's University, Seoul 158-710, Republic of Korea. Electronic address: leemyy@empas.com.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Leem
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005081:Exercise Therapy; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology; D012149:Restraint, Physical; D012265:Ribonucleotides / Q000494:pharmacology; D012420:Running / Q000502:physiology* / Q000523:psychology; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology* / Q000628:therapy
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018697:Nootropic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AMPK; BDNF; chronic restraint stress; learning and memory; treadmill running