Nicotine Modulation of Parasympathetic Cardiac Neurons

描述(申请人提供)：三叉神经和潜水反射是最强大的自主神经反射。电或机械刺激三叉神经会引起包括人在内的动物心率急剧下降，在临床文献中常被称为“三叉神经反射”，在动物研究中常被称为“三叉神经降压反应”。三叉神经心脏反射的一个子集是潜水反射。通过将鼻黏膜暴露在水或空气中的化学刺激物来刺激潜水反射，会引起明显的心动过缓，在一次面部浸泡时心率下降高达51%。然而，夸大的潜水反射被认为与婴儿猝死综合症(SIDS)有关。小岛屿发展中国家是1个月至1岁婴儿死亡的主要原因。吸烟是小岛屿发展中国家的最高风险因素之一，虽然烟草烟雾除尼古丁外还含有许多有害物质，但尼古丁对小岛屿发展中国家尤其令人担忧，因为它能够穿过胎盘并在胎儿体内浓缩，而产前接触尼古丁会削弱新生动物从心肺挑战中复苏的能力。该项目将直接测试三叉神经和俯冲反射中感觉神经元的激活会兴奋心脏迷走神经的假设，这些反射通路是由尼古丁和毒碱胆碱能受体内源性和差异性调节的，确定这种调制发生在反射通路中的哪里，最后确定胎儿接触尼古丁是否会放大心脏迷走神经的这种兴奋。为了检验这些假设，我们将使用对该领域相当新颖的技术。两种新的方法包括利用慢病毒表达增强型黄色荧光蛋白(EYFP)和表达光激活的阳离子通道通道视紫红质-2(ChR2)来识别起源于鼻粘膜的感觉神经元的突触终末，以选择性地光激活这些鼻感觉神经元的纤维和突触终末。公共卫生相关性：项目叙述-公共卫生相关性声明这项工作将解决基本的假设，以了解尼古丁和毒碱胆碱能受体调节脑干内潜水反射的细胞基础和机制，并提出哪些受体和过程因胎儿接触尼古丁而改变，从而增加患心肺疾病(如婴儿猝死综合征)的风险。

DESCRIPTION (provided by applicant): The trigeminocardiac and diving reflexes are among the most powerful autonomic reflexes. Electrical or mechanical stimulation of the trigeminal nerve evokes a dramatic decrease in heart rate in animals including man, and has often been termed the `trigeminocardiac reflex' in the clinical literature, and `trigeminal depressor responses' in animal studies. A subset of the trigeminocardiac reflex is the diving reflex. Stimulation of the diving reflex by exposing the nasal mucosa to water or air-borne chemical irritants evokes a pronounced bradycardia with heart rate decreasing up to 51% upon a single facial submersion. However an exaggerated diving reflex has been implicated in sudden infant death syndrome (SIDS). SIDS is the leading cause of death among infants who are 1 month to 1 year old. One of the highest risk factors for SIDS is cigarette smoking and while tobacco smoke contains a number of deleterious agents in addition to nicotine, nicotine is of particular concern in relation to SIDS due to its ability to cross the placenta and concentrate in the fetus, and prenatal nicotine exposure impairs the ability of newborn animals to resuscitate from cardiorespiratory challenges. This project will directly test the hypotheses that activation of sensory neurons in the trigeminocardiac and diving reflexes excites cardiac vagal neurons, these reflex pathways are endogenously and differentially modulated by nicotinic and muscarinic cholinergic receptors, determine where in this reflex pathway this modulation occurs, and finally whether fetal exposure to nicotine exaggerates this excitation of cardiac vagal neurons. To test these hypotheses we will utilize techniques that are quite novel to this field. Two such new approaches include the identification of the synaptic terminals of sensory neurons originating in the nasal mucosa using lentivirus expression of enhanced yellow fluorescent protein (eYFP), as well as the expression of channelrhodopsin-2 (ChR2), a light activated cation channel, to selectively photoactivate the fibers and synaptic terminals of these nasal sensory neurons. PUBLIC HEALTH RELEVANCE: Project Narrative - Public Health Relevance Statement This work will address hypotheses fundamental to understanding the cellular basis and mechanisms by which nicotinic and muscarinic cholinergic receptors modulate the diving reflex within the brainstem, and will also suggest which receptors and processes are altered by fetal exposure to nicotine that increases the risk of cardiorespiratory diseases such as sudden infant death syndrome (SIDS).