* Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, 1524, Prof. Lineu Prestes Avenue, 05508-900, São Paulo, SP, Brazil.
Exp Physiol. 2014 Mar;99(3):571-85. doi: 10.1113/expphysiol.2013.076752. Epub 2013 Dec 20.
Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/H(+). A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b(+)TH(-)) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP-SAP) into the RTN destroyed Phox2b(+)TH(-) neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP-SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO2) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b(+)TH(-) neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b(+)TH(-) neurons is a plausible cause of the respiratory deficits observed after injection of SSP-SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.
化学感受是大脑调节呼吸以响应组织 CO2/H(+)变化的经典机制。脑干中的一个区域称为梯形核(retrotrapezoid nucleus, RTN)，其中包含一群表达 Phox2b 的谷氨酸能神经元，这些神经元似乎作为重要的化学感受器发挥作用。在本研究中，我们询问破坏表达转录因子 Phox2b 且非儿茶酚胺能的一种 pH 敏感中间神经元（Phox2b(+)TH(-)）是否会影响清醒成年大鼠的呼吸。将神经激肽 P（1 nmol，体积 50 nl）注入 RTN 会增加呼吸频率、潮气量、分钟通气量和平均动脉压。将神经激肽 P 与相思豆毒素 S（SP-SAP）的混合物双侧注入 RTN 会破坏 Phox2b(+)TH(-)神经元，但保留面运动神经元、儿茶酚胺能和 5-羟色胺能神经元以及面神经核下方的腹侧呼吸柱。用 SSP-SAP（0.6 ng，30 nl）双侧抑制 RTN 神经元会降低清醒大鼠的静息通气量和由 CO2 增加（7% CO2）引起的通气量增加，无论是否存在外周化学感受器。在双侧 Phox2b(+)TH(-)神经元损伤约 90%的麻醉大鼠中，用 NMDA（5 pmol，50 nl）急性激活 Bötzinger 复合体、前 Bötzinger 复合体或头侧腹侧呼吸组会诱发正常的心肺输出。总之，将 SSP-SAP 注入 RTN 后观察到的呼吸缺陷可能是 Phox2b(+)TH(-)神经元破坏的原因。我们的结果还表明，RTN 神经元激活了在清醒成年大鼠静息或高碳酸血症条件下控制呼吸的重要促进机制。
