Chronic nicotine and synaptic transmission in brainstem respiratory neurons

脑干呼吸神经元的慢性尼古丁和突触传递

• 批准号: 9919608
• 负责人: Ralph Frank Fregosi
• 金额: $ 38.17万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919608
• 关键词: ARHGEF5 gene; Acetylcholine; Action Potentials; Acute; Adolescence; Age; Animals; Attenuated; Birth; Brain; Brain Stem; Breathing; Carbon Dioxide; Cells; Chronic; Data; Deglutition; Dendrites; Development; Devices; Electronic cigarette; Electrophysiology (science); Experimental Designs; Exposure to; Glutamates; Glycine; Goals; Growth; Homeostasis; Human Milk; Hypercapnia; Immunohistochemistry; In Vitro; Injections; Life; Longevity; Maintenance; Mastication; Measurement; Membrane; Membrane Potentials; Mothers; Motor; Motor Neurons; Muscle; Nervous system structure; Neuroanatomy; Neurons; Neurotransmitter Receptor; Neurotransmitters; Newborn Animals; Nicotine; Nicotinic Receptors; Outcome; Output; Pattern; Physicians; Physiological; Play; Plethysmography; Process; Progress Reports; Property; Protocols documentation; Pump; Rattus; Resistance; Respiration; Role; Smokeless; Structure; Synapses; Synaptic Transmission; System; Techniques; Testing; Time; Tongue; Weaning; Work; critical period; drinking water; electronic cigarette use; experimental study; gamma-Aminobutyric Acid; gender difference; hookah; in utero; in vivo; neonatal period; nervous system development; nicotine exposure; nicotine gum; nicotine patch; nicotine use; nicotine use in pregnancy; patch clamp; postnatal; postsynaptic; prenatal; prenatal cigarette smoking; prenatal exposure; presynaptic; receptor expression; relating to nervous system; respiratory; response; sex; social; stressor; suckling; voltage

Despite a growing body of evidence showing that in utero nicotine exposure leads to aberrant development of brainstem neurons involved in the maintenance of key homeostatic functions such as breathing, the consumption of nicotine via smokeless nicotine delivery devices (e.g., e-cigarettes, water pipes, nicotine patches or gum) more than doubled between 2008-2012. A particular concern is raised by recent studies showing that 30% of pregnant smokers were advised to use nicotine patches or gum by their physician. To date, the majority of the data on nicotine exposure and development of brainstem neurons has focused on how in utero exposure alters the brains of very young neonatal animals. As a result, we do not know if the changes observed with in utero exposure resolve or persist with maturation, or worsen if exposure continues after birth. The specific objective of this application is to test the hypothesis that prenatal and/or postnatal exposure to nicotine alters the structure and function of brainstem neurons that control the muscles of the tongue (hypoglossal motor neurons, XIIMNs), using an in vitro approach, as well as the breathing-related control of the tongue muscles, using an in vivo approach. The tongue muscles participate in breathing, swallowing, suckling and mastication, and therefore are critical for organismal homeostasis. A key focus is whether abnormal development of the tongue muscle motor system is worsened if nicotine exposure continues after birth, or if the alterations persist or are attenuated if exposure ends at weaning. Animals (rats) will be studied at key developmental time points, including the early neonatal period (postnatal day 1 (P1) - P5); the putative critical period for development of brainstem neurons (P10 - P12); the end of adolescence when brain maturation is largely complete (P50 – P60); and after sexual and social maturity (4 – 6 months). Specific Aims: We will use neuroanatomy, immunohistochemistry, patch clamp electrophysiology and in vivo plethysmography and EMG recordings to examine how prenatal and/or postnatal nicotine exposure alters: 1) the dendrite branching pattern and the expression of inhibitory (GABA, glycine) and excitatory (glutamate) neurotransmitter receptors on XIIMNs; 2) development of important neuron membrane properties (resting potential, voltage threshold for spike initiation, etc.), the cell's response to excitatory and inhibitory neurotransmitters; 3) development of the breathing pattern and the function of tongue muscles during normal, quiet breathing and when breathing is increased in response to an acute nicotine challenge or by increasing inspired carbon dioxide. The proposed experiments will result in a comprehensive understanding of how in utero and life-long nicotine exposure alters development of brainstem motoneurons that are critical for survival.

尽管越来越多的证据表明，在子宫内接触尼古丁会导致异常 脑干神经元的发育参与维持关键的稳态功能，例如 呼吸、通过无烟尼古丁输送装置（例如电子烟、 2008 年至 2012 年间，水烟、尼古丁贴片或口香糖）增加了一倍多。特别关注 最近的研究表明，30% 的怀孕吸烟者被建议使用尼古丁 由医生提供的贴剂或口香糖。迄今为止，大多数关于尼古丁暴露和 脑干神经元的发育集中于子宫内暴露如何改变大脑 年轻的新生动物。因此，我们不知道子宫内暴露是否会观察到变化 随着成熟而缓解或持续，或者如果出生后继续接触则恶化。具体目标 该应用程序的目的是测试以下假设：产前和/或产后接触尼古丁会改变 控制舌头肌肉（舌下肌）的脑干神经元的结构和功能 运动神经元（XIIMN），使用体外方法，以及与呼吸相关的控制 舌头肌肉，使用体内方法。舌肌参与呼吸、吞咽、 哺乳和咀嚼，因此对于机体稳态至关重要。一个关键焦点是 如果接触尼古丁，舌头肌肉运动系统的异常发育是否会恶化 出生后持续存在，或者改变持续存在，或者如果暴露在断奶时结束则减弱。 将在关键发育时间点对动物（大鼠）进行研究，包括新生儿早期 （产后第 1 天 (P1) - P5）；脑干神经元发育的假定关键期（P10 - P12）；青春期结束，大脑基本成熟（P50 – P60）；以及之后 性成熟和社会成熟（4 – 6 个月）。具体目标：我们将使用神经解剖学， 免疫组织化学、膜片钳电生理学、体内体积描记法和肌电图 记录以检查产前和/或产后尼古丁暴露如何改变：1）树突 分支模式以及抑制性（GABA、甘氨酸）和兴奋性（谷氨酸）的表达 XIIMN 上的神经递质受体； 2）重要神经元膜特性的发展 （静息电位、尖峰启动的电压阈值等），细胞对兴奋和 抑制性神经递质； 3）呼吸模式和舌头功能的发展 正常、安静呼吸时以及因急性呼吸而增加呼吸时的肌肉 尼古丁挑战或通过增加吸入的二氧化碳。拟议的实验将导致 全面了解子宫内和终生接触尼古丁如何改变发育 对生存至关重要的脑干运动神经元。