title: Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus.
abstract: Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this positive regulation. This evidence might serve in further elucidating the mechanism behind ME-induced cognitive gain.
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan; School of Rehabilitation Science, Health Sciences University of Hokkaido, Kanazawa, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
authors.forename: Koshiro
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan; Department of Anatomy, Showa University School of Medicine, Shinagawa, Hatanodai, Tokyo, 142-8555, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibato
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa, Hatanodai, Tokyo, 142-8555, Japan; Organization for Educational Initiatives, University of Tsukuba, Tsukuba, 305-8577, Ibaraki, Japan.
authors.forename: Randeep
authors.initials: R
authors.lastname: Rakwal
authors.affiliation: Laboratory of Exercise Biochemistry & Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Soya
mesh_terms: D000818:Animals; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D008297:Male; D055495:Neurogenesis; D010805:Physical Conditioning, Animal; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological; D059467:Transcriptome
chemical_list: D003345:Corticosterone