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

• 批准号: 7706447
• 负责人: Jason Quinn Pilarski
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/7706447
• 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

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）：尼古丁是一种跨越血脑屏障，与神经元烟碱乙酰胆碱受体（NACHRS）结合的神经瘤，并改变了人类和非人类动物的脑发育。在中央呼吸道神经元中，有证据表明，在子宫内暴露于尼古丁，会增加快速兴奋性和抑制性神经传递，但是这种神经塑性的解剖学和功能细节尚不清楚。这些数据似乎是自相矛盾的，但是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响应不当的突触输入（例如尼古丁）。因此，本提案旨在研究中央呼吸控制区域神经可塑性的机制，这些机制调节发育过程中慢性尼古丁暴露导致呼吸模式。指导该提议的假设是，产前尼古丁的暴露（PNE）导致甲状腺功能快速兴奋性神经传递在髓质呼吸区域的增加，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“分裂”脑干脊髓制备，并在有或没有压力的谷氨酸受体激动剂和拮抗剂（特定的目标1）以及全细胞斑块夹夹电生理学以检查可能由PNE诱导的突触变化（特定AIM 2）。我们建议，PNE诱导的兴奋性神经传递的增加可能是NACHRS持续激发与体内呼吸控制异常之间的关键联系，尤其是在面临呼吸道挑战时。 公共卫生相关性：研究控制中心呼吸行为的孤立神经网络对于理解更整合的哺乳动物呼吸系统以及对产前和产后发育期间人类呼吸道控制的病理生理状况至关重要。在这里，我们使用了两个与体内呼吸行为相似的不同体外模型，以研究髓质呼吸网络如何通过产前尼古丁的暴露改变。这些知识是理解子宫内暴露于尼古丁（即吸烟）与呼吸调节改变生命的条件之间的众多联系的关键。