Cerpa Verónica J, Aylwin María de la Luz O, Beltrán-Castillo Sebastián, Bravo Eduardo U, Llona Isabel R, Richerson George B, Eugenín Jaime L
1 Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
2 Facultad de Química y Biología, Departamento de Biología, Universidad de Santiago de Chile, USACH, Chile.
Am J Respir Cell Mol Biol. 2015 Oct;53(4):489-99. doi: 10.1165/rcmb.2014-0329OC.
Nicotine may link maternal cigarette smoking with respiratory dysfunctions in sudden infant death syndrome (SIDS). Prenatal-perinatal nicotine exposure blunts ventilatory responses to hypercapnia and reduces central respiratory chemoreception in mouse neonates at Postnatal Days 0 (P0) to P3. This suggests that raphe neurons, which are altered in SIDS and contribute to central respiratory chemoreception, may be affected by nicotine. We therefore investigated whether prenatal-perinatal nicotine exposure affects the activity, electrical properties, and chemosensitivity of raphe obscurus (ROb) neurons in mouse neonates. Osmotic minipumps, implanted subcutaneously in 5- to 7-day-pregnant CF1 mice, delivered nicotine bitartrate (60 mg kg(-1) d(-1)) or saline (control) for up to 28 days. In neonates, ventilation was recorded by head-out plethysmography, c-Fos (neuronal activity marker), or serotonin autoreceptors (5HT1AR) were immunodetected using light microscopy, and patch-clamp recordings were made from raphe neurons in brainstem slices under normocarbia and hypercarbia. Prenatal-perinatal nicotine exposure decreased the hypercarbia-induced ventilatory responses at P1-P5, reduced both the number of c-Fos-positive ROb neurons during eucapnic normoxia at P1-P3 and their hypercapnia-induced recruitment at P3, increased 5HT1AR immunolabeling of ROb neurons at P3-P5, and reduced the spontaneous firing frequency of ROb neurons at P3 without affecting their CO2 sensitivity or their passive and active electrical properties. These findings reveal that prenatal-perinatal nicotine reduces the activity of neonatal ROb neurons, likely as a consequence of increased expression of 5HT1ARs. This hypoactivity may change the functional state of the respiratory neural network leading to breathing vulnerability and chemosensory failure as seen in SIDS.
尼古丁可能将母亲吸烟与婴儿猝死综合征（SIDS）中的呼吸功能障碍联系起来。产前-围产期尼古丁暴露会减弱对高碳酸血症的通气反应，并降低出生后0天（P0）至P3天小鼠新生儿的中枢呼吸化学感受。这表明在SIDS中发生改变并参与中枢呼吸化学感受的中缝神经元可能受到尼古丁的影响。因此，我们研究了产前-围产期尼古丁暴露是否会影响小鼠新生儿中缝隐核（ROb）神经元的活性、电特性和化学敏感性。将渗透微型泵皮下植入5至7天龄的怀孕CF1小鼠体内，持续28天给予酒石酸尼古丁（60 mg kg(-1) d(-1)）或生理盐水（对照）。在新生儿中，通过头出式体积描记法记录通气情况，使用光学显微镜免疫检测c-Fos（神经元活性标志物）或5-羟色胺自身受体（5HT1AR），并在正常碳酸血症和高碳酸血症条件下从脑干切片中的中缝神经元进行膜片钳记录。产前-围产期尼古丁暴露降低了P1-P5时高碳酸血症诱导的通气反应，减少了P1-P3时正常碳酸血症常氧下c-Fos阳性ROb神经元的数量及其在P3时高碳酸血症诱导的募集，增加了P3-P5时ROb神经元的5HT1AR免疫标记，并降低了P3时ROb神经元的自发放电频率，而不影响其对二氧化碳的敏感性或其被动和主动电特性。这些发现表明，产前-围产期尼古丁降低了新生儿ROb神经元的活性，这可能是5HTlARs表达增加的结果。这种活性降低可能会改变呼吸神经网络的功能状态，导致如SIDS中所见的呼吸易损性和化学感受功能衰竭。
