Effects of chronic nicotinic excitation on central glutamatergic control of breat

慢性烟碱兴奋对乳房中枢谷氨酸能控制的影响

基本信息

批准号：
7901363
负责人：
Jason Quinn Pilarski
金额：
$ 7.5万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901363
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Acetylcholine Acute Agonist Animals Bathing Behavior Binding Biological Neural Networks Blood - brain barrier anatomy Brain Brain Stem Brain region Breathing Cells Cervical Chronic Control Animal Coupled Data Development Electrophysiology (science)Equilibrium Exhibits Exposure to Figs - dietary Frequencies Generations Glutamate Receptor Glutamates Human In Vitro Injection of therapeutic agent Knowledge Laboratories Left Life Link Mammals Measures Mediating Methodology Microinjections Modeling Modification Motor Motor Neurons Motor output Muscle N-Methyl-D-Aspartate Receptors N-Methylaspartate Neonatal Nerve Neuraxis Neuronal Plasticity Neurons Neurotransmitters Nicotine Nicotinic Receptors Pathway interactions Pattern Perinatal Exposure Pharmaceutical Preparations Play Population Preparation Presynaptic Terminals Rattus Regulation Research Research Personnel Respiratory Diaphragm Respiratory System Role Saline Slice Spinal Spinal Cord Synapses System Techniques Ventral Roots Whole-Cell Recordings cigarette smoking desensitization fetal tobacco exposure in vitro Model in vivo neonate neurophysiology neurotransmission patch clamp postnatal postsynaptic preBotzinger complex prenatal pressure presynaptic public health relevance relating to nervous system research study respiratory response skills voltage

项目摘要

DESCRIPTION (provided by applicant): Nicotine is a neuroteratogen that crosses the blood brain barrier, binds to neuronal nicotinic acetylcholine receptors (nAChRs), and alters brain development in human and non-human animals. In central respiratory neurons, there is evidence that in utero exposure to nicotine increases both fast excitatory and inhibitory neurotransmission, but the anatomical and functional details of this neuroplasticity are unclear. These data seem paradoxical, but there is growing evidence that many types of central neurons and neural networks respond to inappropriate synaptic input (e.g. nicotine) by adjusting their excitability to achieve the appropriate balance of inhibitory and excitatory neurotransmission. Consequently, the present proposal aims to investigate mechanisms of neural plasticity in central respiratory control regions that regulate breathing pattern resulting from chronic nicotine exposure during development. The hypothesis guiding this proposal is that prenatal nicotine exposure (PNE) leads to an increase in glutamatergic fast excitatory neurotransmission in medullary respiratory regions that generate respiratory rhythm and control the frequency and amplitude of motor output. We will use a "split-bath" brainstem spinal cord preparation with and without pressure microinjections of glutamate receptors agonists and antagonists (Specific aim 1), as well as whole-cell patch clamp electrophysiology to examine synaptic changes that may be induced by PNE (Specific aim 2). We suggest that the PNE-induced increase in excitatory neurotransmission may be a critical link between the persistent excitation of nAChRs and in vivo respiratory control abnormalities, especially when faced with respiratory challenges. PUBLIC HEALTH RELEVANCE: Studying isolated neural networks that control central breathing behavior is fundamental to understanding the more integrated mammalian respiratory system, as well as pathophysiological conditions that effect human respiratory control during prenatal and postnatal development. Here we use two distinct and highly tractable in vitro models that are similar to in vivo breathing behavior to investigate how medullary respiratory networks are altered by prenatal nicotine exposure. This knowledge is key in understanding the numerous links between the in utero exposure to nicotine (i.e., cigarette smoking) and life threatening conditions in which breathing regulation is altered.

描述（由申请人提供）：尼古丁是一种神经致畸剂，可以穿过血脑屏障，与神经元烟碱乙酰胆碱受体（nAChR）结合，并改变人类和非人类动物的大脑发育。在中枢呼吸神经元中，有证据表明，在子宫内接触尼古丁会增加快速兴奋性和抑制性神经传递，但这种神经可塑性的解剖学和功能细节尚不清楚。这些数据看似矛盾，但越来越多的证据表明，许多类型的中枢神经元和神经网络通过调整其兴奋性以实现抑制性和兴奋性神经传递的适当平衡来对不适当的突触输入（例如尼古丁）做出反应。因此，本提案旨在研究中央呼吸控制区域的神经可塑性机制，该机制调节发育过程中长期接触尼古丁导致的呼吸模式。指导该提议的假设是，产前尼古丁暴露（PNE）导致延髓呼吸区谷氨酸快速兴奋性神经传递增加，从而产生呼吸节律并控制运动输出的频率和幅度。我们将使用“分体浴”脑干脊髓制剂，并使用或不使用谷氨酸受体激动剂和拮抗剂的压力显微注射（具体目标 1），以及全细胞膜片钳电生理学来检查 PNE 可能引起的突触变化（具体目标2）。我们认为，PNE 诱导的兴奋性神经传递增加可能是 nAChR 持续兴奋与体内呼吸控制异常之间的关键联系，尤其是在面临呼吸挑战时。公共卫生相关性：研究控制中枢呼吸行为的孤立神经网络对于了解更完整的哺乳动物呼吸系统以及在产前和产后发育过程中影响人类呼吸控制的病理生理条件至关重要。在这里，我们使用两种与体内呼吸行为相似的独特且高度易于处理的体外模型来研究产前尼古丁暴露如何改变髓质呼吸网络。这些知识对于理解子宫内接触尼古丁（即吸烟）与呼吸调节改变的危及生命的情况之间的众多联系至关重要。