Conditional loss of Engrailed1/2 in Atoh1-derived excitatory cerebellar nuclear neurons impairs eupneic respiration in mice.
Conditional loss of Engrailed1/2 in Atoh1-derived excitatory cerebellar nuclear neurons impairs eupneic respiration in mice.
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DOI：
10.1111/gbb.12788
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Heck DH
中科院分区：
文献类型：
--
作者：
Taylor AP;Lee AS;Goedecke PJ;Tolley EA;Joyner AL;Heck DH
小脑在心肺挑战中的作用的证据早已确立，但小脑参与正常呼吸的研究一直没有定论。在这里，我们研究了Atoh 1-En 1/2小鼠小脑神经病理学模型中正常呼吸的时间方面。Atoh 1-En 1/2条件性基因敲除小鼠在兴奋性小脑核神经元中具有发育模式基因Engrailed 1和2的条件性缺失，这导致内侧和中间兴奋性小脑核神经元的亚群缺失。与对照小鼠相比，三个Atoh 1衍生的小脑外核的样品在条件性敲除中没有显示出细胞损失。我们使用全身无限制体积描记法测量了突变动物和对照同窝仔的正常呼吸，并比较了平均呼吸率、变异系数和CV 2（一种内在节律性指标）。线性回归分析显示，Atoh 1-En 1/2条件性敲除与对照同窝仔相比，总体变异性降低（p = 0.021; B = −0.045），内在节律性增加（p < 0.001; B = −0.037），但我们发现基因型对平均呼吸频率没有影响（p = 0.064）。分析还显示，雌性动物的呼吸频率适度降低（p = 0.025; B = −0.82），变异系数增加（p = 0.0036; B = 0.060），CV 2增加，与基因型无关（p = 0.024; B = 0.026）。这些结果表明，小脑参与正常呼吸的节奏控制。我们认为，小脑参与控制CV 2的呼吸是参与协调呼吸与其他口面节律，如吞咽。已经有充分的文献记载，小脑参与控制呼吸过程中的呼吸挑战，如缺氧，但其在正常呼吸中的作用是未知的。在这里，我们报告说，小脑是需要正常的内在节律（即，CV 2）正常呼吸。这种影响与小脑在协调呼吸与其他有节奏的口面运动（如舔液体或搅拌）方面的作用是一致的。
Evidence for a cerebellar role during cardiopulmonary challenges has long been established, but studies of cerebellar involvement in eupneic breathing have been inconclusive. Here we investigated temporal aspects of eupneic respiration in the Atoh1‐En1/2 mouse model of cerebellar neuropathology. Atoh1‐En1/2 conditional knockout mice have conditional loss of the developmental patterning genes Engrailed1 and 2 in excitatory cerebellar nuclear neurons, which leads to loss of a subset of medial and intermediate excitatory cerebellar nuclear neurons. A sample of three Atoh1‐derived extracerebellar nuclei showed no cell loss in the conditional knockout compared to control mice. We measured eupneic respiration in mutant animals and control littermates using whole‐body unrestrained plethysmography and compared the average respiratory rate, coefficient of variation, and the CV2, a measure of intrinsic rhythmicity. Linear regression analyses revealed that Atoh1‐En1/2 conditional knockouts have decreased overall variability (p = 0.021; b = −0.045) and increased intrinsic rhythmicity compared to their control littermates (p < 0.001; b = −0.037), but we found no effect of genotype on average respiratory rate (p = 0.064). Analysis also revealed modestly decreased respiratory rates (p = 0.025; b = −0.82), increased coefficient of variation (p = 0.0036; b = 0.060), and increased CV2 in female animals, independent of genotype (p = 0.024; b = 0.026). These results suggest a cerebellar involvement in eupneic breathing by controlling rhythmicity. We argue that the cerebellar involvement in controlling the CV2 of respiration is indicative of an involvement of coordinating respiration with other orofacial rhythms, such as swallowing. It has been well documented that the cerebellum is involved in controlling respiration during respiratory challenges, such as hypoxia, but its role in eupneic breathing was not known. Here we report that the cerebellum is required for normal intrinsic rhythmicity (i.e., CV2) of eupneic breathing. This type of influence is compatible with a role of the cerebellum in coordinating breathing with other rhythmic orofacial movements, such as fluid licking or whisking.
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影响因子：
3.6
作者：
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通讯作者：
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DOI：
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发表时间：
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期刊：
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