Nicotine Modulation of Parasympathetic Cardiac Neurons

描述（由申请人提供）：三叉神经心反射和潜水反射是最强大的自主神经反射。三叉神经的电刺激或机械刺激引起包括人在内的动物的心率急剧下降，在临床文献中通常称为“三叉心反射”，在动物研究中称为“三叉神经降压反应”。三叉神经心反射的一个分支是潜水反射。通过将鼻粘膜暴露于水或空气传播的化学刺激物来刺激潜水反射，引起明显的心动过缓，在单次面部浸没时心率降低高达51%。然而，过度的潜水反射与婴儿猝死综合征（SIDS）有关。SIDS是1个月至1岁婴儿死亡的主要原因。SIDS的最高风险因素之一是吸烟，而烟草烟雾中除尼古丁外还含有许多有害物质，尼古丁与SIDS的关系特别令人担忧，因为它能够穿过胎盘并集中在胎儿体内，产前尼古丁暴露会损害新生动物从心肺挑战中复苏的能力。本项目将直接测试以下假设：三叉神经心反射和潜水反射中感觉神经元的激活会兴奋心脏迷走神经元，这些反射通路受到烟碱和毒蕈碱胆碱能受体的内源性和差异性调节，确定这种调节发生在该反射通路的何处，以及最终胎儿暴露于尼古丁是否会夸大心脏迷走神经元的这种兴奋。为了验证这些假设，我们将利用这一领域相当新颖的技术。两个这样的新方法包括识别的突触末梢的感觉神经元起源于鼻粘膜使用慢病毒表达的增强型黄色荧光蛋白（eYFP），以及表达的通道视紫红质-2（ChR 2），光激活阳离子通道，选择性地光激活这些鼻感觉神经元的纤维和突触末梢。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，以了解细胞基础和机制，烟碱和毒蕈碱胆碱能受体调节脑干内的潜水反射，也将表明哪些受体和过程被改变胎儿暴露于尼古丁，增加心脏呼吸系统疾病的风险，如婴儿猝死综合征（SIDS）。

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).