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齧歯類を冬眠様状態に誘導する新規神経回路

髙橋, 徹 筑波大学 DOI:10.15068/0002000910

2021.08.03

概要

1.背景
1−1.恒温動物と体温調節中枢
哺乳類や⿃類は恒温動物 homeotherm であり、体温を通常の外気温より⾼く維持している 1,2。多くの環境で外気温は体温より低いため、恒温性 homeothermyを維持するためには、(睡眠中などの)安静期も含め、常に体内で熱を作る必要がある。褐⾊脂肪細胞による熱産⽣や⾻格筋収縮による発熱が主であるが、それ以外にも、恒温動物は脳、⼼臓、肝臓、腎臓および腸などの内臓からも熱を産⽣する 2。体内で能動的に熱を産⽣する特性を内温性 endothermy と呼び、恒温動物は内温動物 endotherm とも呼ばれる。変温動物 poikilotherm(外温動物 ectotherm)である⿂類、両⽣類、爬⾍類の熱産⽣は運動による筋収縮に⼤きく依存し、また体温は環境温度に強く依存するため、低温下では俊敏な動きが困難となる 2。恒温動物の体温は約37℃に常に⼀定に保たれており、常に⽣理機能を⾼く維持し、活発に活動することが可能になっている。この体温の⽬標値のことを「体温のセットポイント」あるいは「設定温度」と呼ぶ 3。(なお、設定温度の定義に関しては諸説あり議論の余地がある 4。本研究においては本研究で使⽤した実験動物の体温が、環境温度が変化してもその温度に近づこうする、概念的な値という意味でこの⾔葉を使⽤した。この定義においては、実験動物の平均的な体温実測値は約37℃であり、安定した実験環境における体温は約37℃であるため、設定温度は37℃付近ということになる。)

恒温(内温)動物は体温を⼀定に保つために、積極的に体内で熱を作る熱産⽣、および積極的に体内の熱を環境へ逃がす熱放散を⾏う。このような⽣体反応は脳内の体温調節中枢を司令塔とする中枢神経系により制御されており、恒温動物の体温調節には、興奮性および抑制性ニューロンから成る複雑な神経回路が関与している 5,6 。体温調節中枢は視床下部の最前⽅に位置する視索前野
(preoptic area : POA)にあると考えられている 5,6。POA には GABA 作動性(抑制性)ニューロンが存在し、抑制性の下⽅性投射をしている(Fig. S1a)。このニューロンが体温調節効果器(⽪膚⾎管、褐⾊脂肪細胞、⾻格筋など)を制御する脳部位へ抑制性に出⼒することで、体温調節に関与する交感神経や運動神経の出⼒レベルを決めていると考えられている 5,6。体温制御に関する、POA- GABA 作動性ニューロンが軸索を送る標的脳部位には背内側視床下部(dorsomedial hypothalamus : DMH)や延髄淡蒼縫線核 (raphe pallidus : RPa)が挙げられる。DMH にはグルタミン酸作動性(興奮性)ニューロンが存在し、 RPa に投射して RPa ニューロンの活動を促進させる 5,6。この DMH→RPa 神経経路が興奮することにより熱産⽣の亢進、および放熱を減少させるための⽪膚⾎管収縮が促進されるため、体温が上昇すると考えられている。体温調節を⽬的とした熱産⽣は主に褐⾊脂肪組織と⾻格筋で⾏われる。褐⾊脂肪組織では代謝性(⾮ふるえ)熱産⽣が⽣じ、⾻格筋ではふるえ熱産⽣(shivering)が⽣じる 6。暑熱環境においては、POA-GABA 作動性ニューロンによる抑制性シグナルが増強し、DMH や RPa のニューロンの活動を低下させた結果、熱産⽣の抑制、および⽪膚⾎管拡張による熱放散の促進が⽣じ、体温を下げる⽅向に調節する 6。寒冷環境においては、POA-GABA 作動性ニューロンによる抑制性シグナルが減弱し、DMH や RPa が脱抑制され、熱産⽣が亢進し、⽪膚⾎管収縮による熱放散が抑制され、体温を上げる⽅向に調節すると考えられている 6。

あらゆる環境温度において体温を維持できる恒温性(内温性)は哺乳類、⿃類に多くの恩恵をもたらしている。地球上における⽣息領域を⼤きく広げることに起因したことから、恒温性の獲得は恒温動物にとっての⽣態学的成功の1つだと考えられている 2。他にも、恒温性は複雑な中枢神経系の発達、酵素反応に適した環境、および⾼い運動能⼒の獲得に貢献している 2。しかし恒温動物は、このような多くの利点の反⾯、エネルギー代謝という観点から⼤きな⽋点を有している。恒温動物は通常、体温維持に多くのエネルギーを消費しているため、基礎代謝率 basal metabolic rate が⾼い⽔準で維持され、変温動物よりも遥かに⾼い基礎代謝を維持し続けなければならない 2。以上のように、われわれヒトを含めた⼤多数の哺乳類は、体温を⼀定に保つための強固な体温制御機構を有する反⾯、体温や代謝を能動的に低下させることはできない。これはすなわち、恒温動物が⽣存するためには、⾼価なエネルギー経費を常に⽀払い続けなくてはならないことを意味している。

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