Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons
Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons
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DOI：
10.1523/jneurosci.4729-07.2008
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发表时间：
2008-03-05
影响因子：
5.3
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
--
作者：
Hodges, Matthew R.;Tattersall, Glenn J.;Richerson, George B.
5-羟色胺能神经元广泛投射到整个CNS并调节许多不同的脑功能。特别重要，但有争议的是5-羟色胺（5-HT）神经元对呼吸和体温调节控制的贡献。为了更好地定义5-HT神经元在呼吸和体温调节中的作用，我们利用了一种独特的条件性基因敲除小鼠，其中Lmx 1b在Pet 1表达细胞（Lmx 1b（f/f/p））中基因缺失，导致中枢5-HT神经元几乎完全缺失。在这里，我们发现，成年Lmx 1b（f/f/p）小鼠的高碳酸血症呼吸反应与野生型小鼠相比降低了50%，而基线通气和低氧呼吸反应是正常的。此外，Lmx 1b（f/f/p）小鼠暴露于4摄氏度的环境温度时迅速变得体温过低，在120分钟内将核心温度降至30摄氏度。这种体温调节失败是由颤抖和非颤抖产热受损引起的，而热敏感知和热量保存是正常的。最后，侧脑室注射5-羟色胺刺激基础通气，并挽救了钝性高碳酸血症的缓解反应。这些数据确定了一个以前未被认识到的作用，5-HT神经元在CO2化学反射，从而增强了反应的其余部分的呼吸网络的CO2。我们的结论是，适当的5-HT系统的功能是特别重要的环境压力的条件下，并有助于显着的高碳酸血症性反应和体温调节冷防御。
Serotonergic neurons project widely throughout the CNS and modulate many different brain functions. Particularly important, but controversial, are the contributions of serotonin (5-HT) neurons to respiratory and thermoregulatory control. To better define the roles of 5-HT neurons in breathing and thermoregulation, we took advantage of a unique conditional knock-out mouse in which Lmx1b is genetically deleted in Pet1-expressing cells (Lmx1b(f/f/p)), resulting in near-complete absence of central 5-HT neurons. Here, we show that the hypercapnic ventilatory response in adult Lmx1b(f/f/p) mice was decreased by 50% compared with wild-type mice, whereas baseline ventilation and the hypoxic ventilatory response were normal. In addition, Lmx1b(f/f/p) mice rapidly became hypothermic when exposed to an ambient temperature of 4 degrees C, decreasing core temperature to 30 degrees C within 120 min. This failure of thermoregulation was caused by impaired shivering and nonshivering thermogenesis, whereas thermosensory perception and heat conservation were normal. Finally, intracerebroventricular infusion of 5-HT stimulated baseline ventilation, and rescued the blunted hypercapnic ventilatory response. These data identify a previously unrecognized role of 5-HT neurons in the CO2 chemoreflex, whereby they enhance the response of the rest of the respiratory network to CO2. We conclude that the proper function of the 5-HT system is particularly important under conditions of environmental stress and contributes significantly to the hypercapnic ventilatory response and thermoregulatory cold defense.