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.

尽管有越来越多的证据表明，在子宫内尼古丁的暴露会导致异常 涉及维持关键稳态功能的脑干神经元的发展，例如 呼吸，通过无烟尼古丁递送设备消费尼古丁（例如，电子烟， 水管，尼古丁斑块或口香糖）在2008 - 2012年之间翻了一番。一个特别的关注 最近的研究表明，建议30％的孕妇使用尼古丁 斑块或牙龈由他们的物理学家。迄今为止，大多数有关尼古丁暴露的数据和 脑干神经元的发展集中在子宫暴露中如何改变非常的大脑 年轻的新生动物。结果，我们不知道在子宫曝光中观察到的变化是否 解决或持续成熟，或者如果出生后继续暴露，则更糟。具体目标 此应用的是检验以下假设，即产前和/或产后暴露于尼古丁 控制舌头肌肉的脑干神经元的结构和功能（垂体 运动神经元，xiimns），使用体外方法以及与呼吸有关的控制 使用体内方法，舌头肌肉。舌头肌肉参与呼吸，吞咽， 哺乳和咀嚼，因此对于有机稳态至关重要。一个重点是 如果尼古丁暴露，舌头肌肉运动系统的异常发育是否恶化 出生后继续进行，或者如果暴露在断奶时持续或衰减，则继续衰减。 动物（大鼠）将在关键的发育时间点进行研究，包括新生儿早期 （产后第1天（P1）-P5）;脑干神经元发展的假定关键时期（P10- p12）;当大脑成熟在很大程度上完成时，青少年的末端（P50 - P60）；之后 性和社会成熟度（4 - 6个月）。具体目的：我们将使用神经解剖学， 免疫组织化学，斑块夹电生理学和体内杂质学和EMG 记录以检查产前和/或产后尼古丁暴露的变化：1）树突 分支模式和抑制性（GABA，甘氨酸）和兴奋性（谷氨酸）的表达 XIIMNS上的神经递质接收器； 2）重要神经元膜特性的发展 （静止的电位，尖峰倡议的电压阈值等），该细胞对兴奋性的反应和 抑制性神经递质； 3）呼吸模式的发展和舌头的功能 正常，安静的呼吸和呼吸时，肌肉响应急性时 尼古丁挑战或增加受启发的二氧化碳。提出的实验将导致 对子宫和终身尼古丁暴露的全面了解如何改变 对生存至关重要的脑干运动神经元。