理学療法ジャーナル51巻7号

2017年07月発行

講座 運動と分子生物学・3

運動の認知・神経機能への影響

著者： 征矢茉莉子¹ 征矢英昭¹

所属機関： ¹筑波大学体育系運動生化学・神経内分泌学研究室ヒューマン・ハイ・パフォーマンス先端研究センター・スポーツ神経科学研究室

ページ範囲：P.626 - P.631

はじめに

　運動は末梢機能のみならず中枢にも作用し，認知機能を高める効果を有する．なかでも，学習・記憶を担う海馬は生涯にわたり新たな神経が生まれる（成体海馬神経新生，adult hippocampal neurogenesis：AHN）ことから可塑性が高く運動効果を享受しやすい脳部位として知られており，運動はAHNを高めることや，海馬におけるエネルギー代謝に影響を及ぼすことで海馬機能を向上させることが明らかとなってきた．このことから，最近では全米スポーツ医学会（American College of Sports Medicine：ACSM）が「exercise is medicine（運動は副作用のない薬）」と提唱するように，世界的に社会問題となる生活習慣病や認知症患者，また精神疾患患者で低下した認知機能に対する運動処方の開発に多くの期待が寄せられており，運動が認知機能を高める脳機構の解明が不可欠である．

　本稿では，運動が高める海馬可塑性や認知機能向上の背景にあるAHNおよび海馬内糖代謝について概説する．

参考文献

1）Eriksson PS, et al：Neurogenesis in the adult human hippocampus. Nat Med 4：1313-1317, 1998

2）Clelland CD, et al：A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325：210-213, 2009

3）Ohiwa N, et al：Possible inhibitory role of prolactin-releasing peptide for ACTH release associated with running stress. Am J Physiol Regul Integr Comp Physiol 292：R497-R504, 2007

4）Soya H, et al：Threshold-like pattern of neuronal activation in the hypothalamus during treadmill running：establishment of a minimum running stress（MRS）rat model. Neurosci Res 58：341-348, 2007

5）Soya H, et al：BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358：961-967, 2007

6）van Praag H, et al：Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96：13427-13431, 1999

7）O'Brien JT, et al：Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer's disease. Br J Psychiatry 168：679-687, 1996

8）First M, et al：The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression. J Mol Neurosci 45：246-255, 2011

9）Tata DA, Anderson BJ：The effects of chronic glucocorticoid exposure on dendritic length synapse numbers and glial volume in animal models：implications for hippocampal volume reductions in depression. Physiol Behav 99：186-193, 2010

10）Okamoto M, et al：Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis. Proc Natl Acad Sci U S A 109：13100-13105, 2012

11）Inoue K, et al：Long-term mild exercise training enhances hippocampus-dependent memory in rats. Int J Sports Med 36：280-285, 2015

12）Nishijima T, et al：Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise. J Appl Physiol 112：197-203, 2012

13）Inoue K, et al：Long-term mild, rather than intense, exercise enhances adult hippocampal neurogenesis and greatly changes the transcriptomic profile of the hippocampus. PLoS One 10：e0128720, 2015

14）Vance JE, et al：Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol 16：193-212, 2005

15）Pfrieger FW：Outsourcing in the brain：do neurons depend on cholesterol delivery by astrocytes? Bioessays 25：72-78, 2003

16）Kimoto T, et al：Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons：N-methyl-D-aspartate and calcium-dependent synthesis. Endocrinology 142：3578-3589, 2001

17）Bracko O, et al：Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 32：3376-3387, 2012

18）Folli F, et al：Insulin receptor substrate-1（IRS-1）distribution in the rat central nervous system. J Neurosci 14：6412-6422, 1994

19）Myers MG, et al：IRS-1 is a common element in insulin and insulin-like growth factor-Ⅰ signaling to the phosphatidylinositol 3'-kinase. Endocrinology 132：1421-1430, 1993

20）Zheng WH, Quirion R：Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. Neurochem 89：844-852, 2004

21）Yirmiya R, et al：Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25：181-213, 2011

22）Benarroch EE：Glycogen metabolism：metabolic coupling between astrocytes and neurons. Neurology 74：919-923, 2010

23）Tsacopoulos M and Magistretti PJ：Metabolic coupling between glia and neurons. J Neurosci 16：877-885, 1996

24）Newman LA, et al：Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS One 6：e28427, 2011

］-5-chloro-N-［2-hydroxy-3-（methoxymethylamino）-3-oxo-1-（phenylmethyl）propyl］-1H-indole-2-carboxamide）. J Pharmacol Exp Ther 321：45-50, 2007

26）Duran J, et al：Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain. J Cereb Blood Flow Metab 33：550-556, 2012

27）Suzuki A, et al：Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144：810-823, 2011

28）Boury-Jamot B, et al：Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol Psychiatry 21：1070-1076, 2016

29）Lezi E, et al：Lactate administration reproduces specific brain and liver exercise-related changes. J Neurochem 127：91-100, 2013

30）Yang J, et al：Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci U S A 111：12228-12233, 2014

31）Cukierman T, et al：Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies. Diabetologia 48：2460-2469, 2005

32）Umegaki H, et al：Cognitive dysfunction：an emerging concept of a new diabetic complication in the elderly. Geriatr Gerontol Int 13：28-34, 2013

33）Shima T, et al：Differential effects of type 2 diabetes on brain glycometabolism in rats：focus on glycogen and monocarboxylate transporter 2. J Physiol Sci［Epub ahead of print］, 2016

34）Alomari MA, et al：Forced and voluntary exercises equally improve spatial learning and memory and hippocampal BDNF levels. Behav Brain Res 247：34-39, 2013

35）Pereira AC, et al：An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 104：5638-5643, 2007

36）Shima T, et al：Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes. Diabetologia 60：597-606, 2017

37）Matsui T, et al：Brain glycogen supercompensation following exhaustive exercise. J Physiol 590：607-616, 2012