Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis.
Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis.
复制标题
肌萎缩侧索硬化症小鼠模型的日常温度调节缺陷。
DOI：
10.1016/j.expneurol.2018.07.008
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发表时间：
2019
影响因子：
5.3
通讯作者：
Schwartz,WilliamJ
中科院分区：
文献类型：
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作者：
Braun,MaurineC;Castillo-Ruiz,Alexandra;Indic,Premananda;Jung,DaeYoung;Kim,JasonK;BrownJr,RobertH;Swoap,StevenJ;Schwartz,WilliamJ
目前对肌萎缩性侧索硬化症家族型发病机制的理解，已经通过对转基因小鼠的研究得到了帮助，这些小鼠过度表达了人类cuzn -超氧化物歧化酶（SOD1）基因的突变形式。虽然运动神经元中的SOD1突变决定了疾病的发病，但其他非细胞自主因素对疾病进展至关重要，并且改变的能量代谢被认为是一个促成因素。由于实验室小鼠消耗的大部分能量用于保护体温（Tb），我们分析了携带人类sod1基因G93A突变的转基因小鼠的体温调节，使用可植入的温度数据记录仪连续记录温度，最长可达85 天。在室温（22 °C）环境温度下，与C57BL/6J对照组相比，G93A小鼠表现出每日节律幅度的降低，这是由于在光-暗循环的黑暗（行为活跃）阶段tb值降低所致。该缺陷出现在85-99 日龄，大约在症状出现的年龄（通过握力评估），远远早于可观察到的虚弱和体重减轻，并且不能通过运动活动水平下降或食物消耗来解释。在热中性（29 °C）环境温度下饲养，部分修复了缺陷，但与年龄有关（仅在年龄为100 日龄的动物中），这表明老年小鼠的缺陷部分是由于疾病进展时“外周”产热器官的产热不足。在年轻的小鼠中，我们发现冷诱导的产热和能量消耗是完整的，这表明最初的“中枢”缺陷可能位于室旁下区，涉及从下丘脑视交叉上核的生物钟到前脑温度调节回路的神经输出通路。
Current understanding of the pathogenesis of the familial form of amyotrophic lateral sclerosis has been aided by the study of transgenic mice that over-express mutated forms of the human CuZn-superoxide dismutase (SOD1) gene. While mutant SOD1 in motor neurons determines disease onset, other non-cell autonomous factors are critical for disease progression, and altered energy metabolism has been implicated as a contributing factor. Since most energy expended by laboratory mice is utilized to defend body temperature (Tb), we analyzed thermoregulation in transgenic mice carrying the G93A mutation of the humanSOD1gene, using implantable temperature data loggers to continuously record Tbfor up to 85 days. At room (22 °C) ambient temperature, G93A mice exhibited a diminished amplitude of the daily Tbrhythm compared to C57BL/6J controls, secondary to decreased Tbvalues during the dark (behaviorally active) phase of the light-dark cycle. The defect arose at 85–99 days of age, around the age of symptom onset (as assessed by grip strength), well before observable weakness and weight loss, and could not be accounted for by decreased levels of locomotor activity or food consumption. Housing under thermoneutral (29 °C) ambient temperature partially rescued the defect, but age-dependently (only in animals >100 days of age), suggesting that the deficit in older mice was due in part to inadequate thermogenesis by “peripheral” thermogenic organs as the disease progressed. In younger mice, we found that cold-induced thermogenesis and energy expenditure were intact, hinting that an initial “central” defect might localize to the subparaventricular zone, involving neural output pathways from the circadian clock in the hypothalamic suprachiasmatic nucleus to forebrain thermoregulatory circuitry.