制度:新 ; 報告番号:甲3874号 ; 学位の種類:博士(スポーツ科学) ; 授与年月日:2013/3/15 ; 主論文の冊数:1 ; 早大学位記番号:新6242Waseda Universit

林 政賢

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2013年 1月 8日   博士学位論文審査報告書  大学名    早稲田大学 研究科名   スポーツ科学研究科 申請者氏名  林 政賢 学位の種類  博士（スポーツ科学） 論文題目   日常運動が行動性体温調節に及ぼす影響   The effect of daily exercise on behavioral thermoregulation in mice  論文審査員  主査 早稲田大学教授 彼末一之 医学博士、工学博士 （大阪大学） 副査 早稲田大学教授 永島 計 博士（医学） （京都府立医科大学） 副査 早稲田大学教授 樋口 満 教育学博士 （東京大学）    日常的な運動や運動トレーニングが発汗や皮膚血管拡張反応等の暑熱下での自律性体温調節能を増加させることはよく知られている．しかしながら、体温調節に最も重要である暑熱逃避などの行動性体温調節に対する効果はよく知られていない．申請者は実験動物を用いて行動性体温調節を評価する実験システムを開発し、日常運動の効果を評価するとともに、その脳内メカニズムの一部を明らかにした。下記にその概略を示す．  高浸透圧血症は脱水時に見られる体液変化であり、暑熱下での様々な体温調節反応を減弱させる強い要因であると考えられている．研究では高張食塩水を皮下投与したマウスを用いて実験を行った．実際には，正常(154 mM、IS)あるいは高張食塩水(2500 mM、HS)を皮下注射(1ml/100gの体重)し、約 15 mosmol/kg•H20の血漿浸透圧の上昇を得た．日常運動の効果を見るために、１群のマウスではケージ内に回転ホイールをおき自由に運動をさせ、他群のマウスでは回転ホイールを与えずに飼育を行った．  行動性体温調節は、実験ボックスの底に温度コントロールが可能な 5つのペルチエ板をおき様々な温度負荷を与えた際の行動様式を観察することによって評価した．温度負荷として暑熱負荷時にペルチエ板１つが冷却される報酬行動設定、ペルチエ板の温度がランダムに変化するモザイク設定の２種類の実験設定で行った．  高張食塩水投与は暑熱下の報酬行動回数を著明に低下させ、それとともにマウスの体温が上昇した．このことは行動性体温調節の減弱が脱水時に生じ、脱水時の高体温は行動性体温調節の低下に一部起因することを示唆している．しかしながら、回転ホイールを与えたマウスは血漿浸透圧が上昇していたにも関わらず報酬行動回数の減少が認められなかった．  モザイク設定にマウスをおいた際は、高張食塩水投与による影響は見られなかった．しかし回転ホイールを与えられたマウスは、より低温の温度環境を求めて移動する行動が認められた．このことは日常運動が温度嗜好性を変化させる可能性を示唆している．  以上の結果は、日常運動は高浸透圧血症による行動性体温調節への影響を弱め、暑さや脱水時においても体温をよりうまく維持できる機能を与えると考えられる．また、このためにより低い温度環境への嗜好性を獲得するのではないかと考えられる．  申請者はさらに、脳の組織科学的解析を行うことにより、行動性体温調節と、それに対する運動の効果の脳内メカニズムを探索した．暑熱負荷時に、日常運動を行ったマウスでは視床下部の室傍核(PVN)、扁桃核中央部(CeM)、視索前野/前視床下部(PO/AH)により強く、神経活動の指標となる Fosタンパクの発現が、非運動マウスに比較して強く認められた．また、これらの変化は暑熱下の寒冷報酬行動を行っている際にも強く認められた．  以上の結果より、日常運動がマウスの暑熱下行動性体温調節反応を強く修飾すること、また、そのメカニズムに視床下部が関与している可能性を明らかにした。これらの知見は基本的な生理学の知識を広げるとともに、温暖化が問題になっている現代での暑さ対策のための知識として非常に重要な知見といえる．しかしながら、未だ行動性体温調節の脳内機序、および日常運動の効果の全容が明らかにされたとはいえず、申請者による当該領域のさらなる研究の発展が期待される．  本論文の内容が掲載された学術論文は以下の通りである。 Cheng-Hsien Lin, Ken Tokizawa, Mayumi Nakamura, Yuki Uchida, Hisae Mori, Kei Nagashima.  Hyperosmolality in the plasma modulates behavioral thermoregulation in mice: The quantitative and multilateral assessment using a new experimental system. Physiology and Behavior, 105, 536-543, 2012.  以上より、本論文が優れた学術的価値を有するものであると判断し、博士 (スポーツ科学) の学位を授与するに十分値するものと認める。  以上 

Effect of daily exercise on behavioral thermoregulation in mice

Waseda University博士（スポーツ科学）制度:新 ; 報告番号:甲3874号 ; 学位の種類:博士(スポーツ科学) ; 授与年月日:2013/3/15 ; 主論文の冊数:1 ; 早大学位記番号:新6242textthesi

Rin, Chenshen

36938

林, 政賢

Waseda University Repository

早稲田大学審査学位論文 博士（スポーツ科学） 概要書  The effect of daily exercise on behavioral thermoregulation in mice    日常運動が行動性体温調節におよぼす影響  ２０１３年１月  早稲田大学大学院 スポーツ科学研究科 林 政賢  Lin, Cheng-Hsien 研究指導教員： 彼末 一之 教授  II. Abstract The aims of my study were to develop an experimental system to assess behavioral thermoregulation, and establish animal model to clarify the influence of dehydration on it.  Moreover, I planned to evaluate the effect of chronic exercise on behavioral thermoregulation and the neural mechanisms.  I conducted three studies to fulfill the aims. Study 1.  Hyperosmolality in the plasma modulates behavioral thermoregulation in mice: the quantitative and multilateral assessment using a experimental system.  We have developed a new system to evaluate behavioral thermoregulation and the effect of plasma hyperosmolality on the behavioral responses to heat in mice.  The system consisted of Plexiglas box (dimensions: 50×12×19 cm) with five computer-controlled Peltier boards (dimensions: 10×10 cm) at the bottom.  We set the system to two different settings by changing the operating program as follows: a) an operant behavior setting, in which the temperature of each board was first set at 39°C, and the right-end board was changed to 20°C within 1 min of a mouse moving on the left-end board; and b) a temperature gradient setting, in which each board was randomly set at 15°C, 22°C, 28°C, 35°C, or 39°C with a 6-min interval.  Mice received subcutaneously (s.c.) injection of isotonic or hypertonic saline (154 mM (IS group) or 2,500 mM (HS group), 10 ml/kg body wt).  The mice were exposed to each setting for 90 min.  In the operant setting, the HS group had fewer operant behavior counts than the IS group (11 ± 5 and 25 ± 4 counts, respectively; P<0.05) and an increase in body temperature (1.6 ± 0.4°C vs. 0.0 ± 0.2°C, respectively; P< 0.05).  In the gradient setting, both groups had greater counts at a board temperature of 35°C.  The system enabled us to evaluate and compare the behavioral responses to the two different settings.  In addition, plasma hyperosmolality might be a signal to change thermal preferences and maintain a higher body temperature. Study 2.  Effect of daily exercise on heat-escape/cold-seeking behavior and thermal preference in mice: exercise training modulates feeling of hot?  We tested chronic exercise in mice augments heat tolerance by modulating behavioral thermoregulatory responses.  Mice housed with or without a running-wheel for 8 weeks (WR and NWR groups, n=47 and 40, respectively) were used.  Implanted a body temperature (Tb) measurement device, the mice received s.c. injection of isotonic- or hypertonic-saline (1 ml/100 g of body wt; 154 or 2,500 mM, IS or HS subgroup) and were placed in a box with 5 Peltier boards at the bottom.  Three experiments were conducted for 90 min, using different controlling programs of the board temperatures: 1) constant board temperatures of 28°C or 39°C; 2) an operant-behavior setting: each board was set at 39°C and the right-end board was changed to 20°C within 60 s only when the mouse moved to the left-end board; and 3) a thermal mosaic setting: each board was set at either 15°C, 22°C, 28°C, 35°C, or 39°C with a 6-min interval.  In Experiment 1, Tb in both subgroups of the WR group became higher than that in the NWR group.  In Experiment 2, the NWR group showed smaller operant counts in the HS subgroup than the IS subgroup; however, the WR group did not.  In Experiment 3, the WR group preferred lower temperatures than the NWR group without any differences between the subgroups (e.g., 33.4 ± 0.3°C and 34.7 ± 0.1°C in IS groups).  Exercise training may alter thermal preference and behavioral responses, thereby increases thermal tolerance, diminishing the effect of dehydration. Study 3.  Facilitating c-Fos expression in the POAH of the mouse brain by heat stress or hyperosmolality can be potentiated by chronic exercise.  Recent studies have used the expression of immediate early gene such as c-Fos to demonstrate that exercise increases the neural activity in the hippocampal neurons of mouse brain.  It is currently unknown whether the basal c-Fos expression as well as the increased c-Fos expression caused by heat exposure and/or salt loading in the brain can be affected by chronic exercise.  The purpose of this study was to test the hypothesis in mice by using a newly developed device.  Mice were divided into two groups: one group had free access to running wheel for 8 weeks (WR) and the other had no access (NWR).  After subcutaneous injection (1 ml/100 g of body weight) of either normal (154 mM, IS) or hypertonic saline (2,500 mM, HS), each mouse was placed in a behavior box with 5 peltier boards at the bottom, where a) thermal mosaic (temperature of each board was randomly chosen among set at 15°C, 22°C, 28°C, 35°C, or 39°C; mice could select preferable position while the temperature setting was changed each 6 min) or b) operant behavior available (the temperature of each was set at 39°C; one board temperature was changed to 20°C within 60 second when a mouse moved to a specific board).  In the result, when the operant heat escape/cool seeking behavioral setting was unavailable, we could assess overall autonomic response to heat.  Both the basal c-Fos expression and the increased c-Fos expressions caused by heat exposure and/or salt loading in the preoptic are/anterior hypothalamus (POAH), but not in the paraventricular nucleus (PVN) or in the central amygdaloid nucleus (CeM), of WR mice were significantly higher than those of the NWR mice.  Additionally, when the heat escape/cool seeking behavioral setting was available, both the basal c-Fos expression and the c-Fos overexpression induced by heat exposure and/or salt loading in both the POAH and the PVN, but not in the CeM, of the exercise mice were significantly higher than those of the sedentary mice. In experiment 3, during a thermal mosaic setting, the same results as those of the operant behavioral setting were observed. It can be derived from the foregoing results that (i) chronic exercise (voluntary wheel running) is able to induce an upward shift in the basal c-Fos expression in the POAH, but not in the PVN or in the CeM, of the mouse brain; (ii) when the operant behavior setting is unavailable, heat-induced and/or salt loading-induced c-Fos overexpressions in the POAH, but not in the PVN or in the CeM, are significantly potentiated by chronic exercise; and (III) when an operant behavior setting or a thermal mosaic setting is available, heat exposure-induced and/or salt loading-induced c-Fos overexpressions in both the POAH and the PVN, but not in the CeM, of mouse brain are significantly enhanced by chronic exercise. Thus, it appears that the POAH is involved in autonomic thermoregulation, whereas both POAH and PVN are involved in behavioral thermoregulation. Chronic exercise induces an upward shift in the basal c-Fos expression and enhances c-Fos overexpression caused by heat or salt loading in the mouse hypothalamus. 

日常運動が行動性体温調節におよぼす影響 : 早稲田大学審査学位論文博士(スポーツ科学)

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Effect of daily exercise on behavioral thermoregulation in mice

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