Isoflurane Exposure in Juvenile Caenorhabditis elegans Causes Persistent Changes in Neuron Dynamics
Isoflurane Exposure in Juvenile Caenorhabditis elegans Causes Persistent Changes in Neuron Dynamics
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异氟醚暴露对秀丽隐杆线虫幼鱼神经元动力学的影响
DOI：
10.1097/aln.0000000000003335
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发表时间：
2020-05
期刊：
影响因子：
8.8
通讯作者：
Gregory S. Wirak;C. Gabel;C. Connor
中科院分区：
文献类型：
--
作者：
Gregory S. Wirak;C. Gabel;C. Connor
背景：动物研究表明，在神经发育过程中暴露于麻醉剂可导致持续的行为障碍。这些影响背后的神经元功能的变化还不完全清楚。秀丽隐杆线虫非常适合于麻醉后对神经元活动影响的功能成像。本研究旨在研究C. elegans运动方法：C.线虫在神经发育关键的L1幼虫阶段暴露于8%异氟烷3小时。在成年早期和晚期评估运动。自发活动内的运动命令interneuron电路使用共聚焦和光片显微镜的钙敏感的荧光团GCaMP 6s测量。结果：C.暴露于异氟烷的秀丽线虫表现出自发逆转行为的衰减，在动物的整个生命周期中持续存在（逆转/分钟：未治疗的成年早期，1.14 ± 0.42，与异氟烷暴露的成年早期，0.83 ± 0.55;未治疗的成年晚期，1.75 ± 0.64，与异氟烷暴露的成年晚期，1.14 ± 0.68;分别为P = 0.001和0.006; n > 50只动物轨道/条件）。同样，异氟烷暴露改变了指令中间神经元AVA的活动动力学，其介导爬行逆转。发现AVA在活动状态之间转换的速率增加。这些麻醉诱导的效应随着年龄的增长而更加明显（活动状态转换时间：未治疗的成年早期，2.5 ± 1.2，与异氟烷暴露的成年早期，1.9 ± 1.3;未治疗的成年晚期，4.6 ± 3.0，与异氟烷暴露的成年晚期，3.0 ± 2.4; P分别为0.028和0.008; n >从超过15只动物/条件获得的35个痕迹）。在整个命令中间神经元回路中观察到类似的影响，表明异氟烷暴露改变了整个系统的行为爬行状态之间的转换速率。这些作用通过FoxO转录因子daf-16内的功能缺失突变和雷帕霉素介导的雷帕霉素靶点（mTOR）抑制机制来调节。结论：改变的运动行为和活动动力学表明对C。在发育期暴露于异氟烷后，这些作用通过daf-16或mTOR活性的丧失来调节，这与应激反应途径的病理激活一致。秀丽隐杆线虫在第一幼虫阶段暴露于异氟烷3 h导致自发爬行逆转行为终身衰减。这些影响与持续改变的活动动力学的命令中间神经元介导爬行逆转。潜在的潜在机制的遗传解剖表明，这些影响是由daf-16或雷帕霉素活性的机械靶点的损失调节的，与应激反应途径的持续病理激活一致。
Background: Animal studies demonstrate that anesthetic exposure during neurodevelopment can lead to persistent behavioral impairment. The changes in neuronal function underlying these effects are incompletely understood. Caenorhabditis elegans is well suited for functional imaging of postanesthetic effects on neuronal activity. This study aimed to examine such effects within the neurocircuitry underlying C. elegans locomotion. Methods: C. elegans were exposed to 8% isoflurane for 3 h during the neurodevelopmentally critical L1 larval stage. Locomotion was assessed during early and late adulthood. Spontaneous activity was measured within the locomotion command interneuron circuitry using confocal and light-sheet microscopy of the calcium-sensitive fluorophore GCaMP6s. Results: C. elegans exposed to isoflurane demonstrated attenuation in spontaneous reversal behavior, persisting throughout the animal’s lifespan (reversals/min: untreated early adulthood, 1.14 ± 0.42, vs. isoflurane-exposed early adulthood, 0.83 ± 0.55; untreated late adulthood, 1.75 ± 0.64, vs. isoflurane-exposed late adulthood, 1.14 ± 0.68; P = 0.001 and 0.006, respectively; n > 50 animal tracks/condition). Likewise, isoflurane exposure altered activity dynamics in the command interneuron AVA, which mediates crawling reversals. The rate at which AVA transitions between activity states was found to be increased. These anesthetic-induced effects were more pronounced with age (off-to-on activity state transition time (s): untreated early adulthood, 2.5 ± 1.2, vs. isoflurane-exposed early adulthood, 1.9 ± 1.3; untreated late adulthood, 4.6 ± 3.0, vs. isoflurane-exposed late adulthood, 3.0 ± 2.4; P = 0.028 and 0.008, respectively; n > 35 traces acquired from more than 15 animals/condition). Comparable effects were observed throughout the command interneuron circuitry, indicating that isoflurane exposure alters transition rates between behavioral crawling states of the system overall. These effects were modulated by loss-of-function mutations within the FoxO transcription factor daf-16 and by rapamycin-mediated mechanistic Target of Rapamycin (mTOR) inhibition. Conclusions: Altered locomotive behavior and activity dynamics indicate a persistent effect on interneuron dynamics and circuit function in C. elegansafter developmental exposure to isoflurane. These effects are modulated by a loss of daf-16 or mTOR activity, consistent with a pathologic activation of stress-response pathways. Exposure of Caenorhabditis elegans to isoflurane for 3 h during the first larval stage results in lifelong attenuation in spontaneous crawling reversal behavior. These effects correlate with persistently altered activity dynamics of command interneurons mediating crawling reversals. Genetic dissection of potential underlying mechanisms reveals that these effects are modulated by a loss of daf-16 or mechanistic target of rapamycin activity, consistent with a persistent pathologic activation of stress-response pathways.