title: Heat stress-induced memory impairment is associated with neuroinflammation in mice.
abstract: BACKGROUND
  Heat stress induces many pathophysiological responses and has a profound impact on brain structure. It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans. Although the effects of heat stress have long been studied, the mechanisms by which heat stress affects brain structure and cognition not well understood.
  
  
  METHODS
  In our longitudinal study of mice exposed to heat over 7, 14, or 42 days, we found that heat stress time dependently impaired cognitive function as determined by Y-maze, passive avoidance, and novel object recognition tests. To elucidate the histological mechanism by which thermal stress inhibited cognitive abilities, we examined heat stress-induced inflammation in the hippocampus.
  
  
  RESULTS
  In mice subjected to heat exposure, we found: 1) an increased number of glial fibrillary acid protein (GFAP)- and macrophage-1 antigen (Mac-1)-positive cells, 2) up-regulated nuclear factor (NF)-κB, a master regulator of inflammation, and 3) marked increases in cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokine interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the mouse hippocampus. We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression. Moreover, in heat-exposed mice, we found that the number of cells positive for doublecortin (DCX), a marker of neurogenesis, was significantly decreased compared with control mice. Finally, anti-inflammatory agent minocycline inhibited the heat stress-induced cognitive deficits and astogliosis in mice.
  
  
  CONCLUSIONS
  Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.
authors.affiliation: Department of Life and Nanopharmaceutical Science, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. wonil@khu.ac.kr.
authors.forename: Wonil
authors.initials: W
authors.lastname: Lee
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA. hominmoon@mclean.harvard.edu.|Department of Biochemistry, College of Medicine, Konyang University, Daejeon, 302-718, Republic of Korea. hominmoon@mclean.harvard.edu.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. kimhyogeun@khu.ac.kr.
authors.forename: Hyo Geun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Formulae Pharmacology, School of Oriental Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam, 461-701, Republic of Korea. ophmgreengrass@hanmail.net.
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Life and Nanopharmaceutical Science, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. msohok@khu.ac.kr.|Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. msohok@khu.ac.kr.
authors.forename: Myung Sook
authors.initials: MS
authors.lastname: Oh
mesh_terms: D000818:Animals; D003072:Cognition Disorders; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D018882:Heat Stress Disorders / Q000150:complications*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006358:Hot Temperature / Q000009:adverse effects; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009443:Neuritis / Q000209:etiology* / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000503:physiopathology; D055495:Neurogenesis / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2