Consequences of Perinatal Nicotine Exposure on Functional Brainstem Development

围产期尼古丁暴露对功能性脑干发育的影响

基本信息

批准号：
10752337
负责人：
Mackenna Wollet
金额：
$ 3.77万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752337
关键词：
3-Dimensional Acetylcholine Acute Adult Affect Animal Model Auditory Auditory Brainstem Responses Auditory Perceptual Disorders Auditory area Auditory system Binaural Birth Brain Brain Stem Brain region Cell Nucleus Central Auditory Processing Disorder Child Chronic Cigarette Cochlea Detection Development Dyes Electric Capacitance Electronic cigarette Electrophysiology (science)Equilibrium Feedback Fiber Functional disorder Future Glutamate Receptor Glutamates Hearing Hearing Tests Hearing problem Hippocampus Human Development Immunohistochemistry Impairment Incidence Individual Infant Location Longevity Measures Medial Mediating Modeling Mus Neurons Nicotine Nicotinic Receptors Noise Perinatal Perinatal Exposure Peripheral Phenotype Physiology Presynaptic Terminals Process Rattus Reporting Research Risk Rodent Role Sensory Signal Transduction Smoker Sound Localization Structure Sudden infant death syndrome Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Up-Regulation Visualization Western Blotting Whole-Cell Recordings Work auditory processing cholinergic cigarette smoking combustible cigarette critical period electronic cigarette use experience exposure to cigarette smoke glutamatergic signaling hearing loss risk in vivo insight neural nicotine exposure otoacoustic emission patch clamp postnatal postnatal development postsynaptic prenatal prenatal exposure prenatal nicotine exposure presynaptic receptor expression reconstruction response smoking during pregnancy sound transmission process trapezoid body

项目摘要

PROJECT SUMMARY Prenatal exposure to cigarette smoke increases the risk of sudden infant death syndrome as well as developmental deficits in the brain that persist into adulthood. Sensory impairments have been observed, notably in the auditory system, following prenatal cigarette exposure. Due to the increasing popularity of e-cigarettes, the need for research into prenatal exposure to nicotine alone is becoming increasingly important. The critical period of mouse auditory development occurs after birth, allowing for perinatal nicotine exposure to accurately model prenatal nicotine exposure on auditory system phenotypes. In PNE models, disrupted glutamatergic signaling in the auditory cortex and impaired temporal processing in an auditory startle test has been reported. However, the cellular mechanisms whereby perinatal nicotine exposure (PNE) impairs auditory development and central auditory processing are currently unknown. In the auditory system, cholinergic signaling is necessary for peripheral and central auditory processes. Recent work demonstrates the importance of nicotinic acetylcholine receptors in signal-in-noise detection in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem. The alpha 7 nicotinic acetylcholine receptor (α7 nAChR), essential for glutamatergic synapse development in the hippocampus and cortex, is highly expressed in the MNTB during early postnatal development. Utilizing the large glutamatergic Calyx of Held synapse of the MNTB, the proposed studies aim to investigate the effect of PNE on structural and functional development of the calyx terminal, MNTB synapse, and central auditory processing. The central hypothesis is that PNE increases α7 nAChR expression and its chronic activation impairs glutamatergic synapse development in the MNTB resulting in central auditory deficits. Due to the crucial role of MNTB in binaural processing, it is important to examine how the MNTB is affected by PNE during auditory development to understand auditory processing disorders in children prenatally exposed to nicotine. Aim 1 examines developmental expression of nAChRs at the calyx-MNTB synapse and the effect of PNE on nAChR expression using patch-clamp electrophysiology, immunohistochemistry, and western blot. Aim 2 investigates the developmental impact of PNE on the structure and function of calyx of Held synapse. Direct presynaptic recordings of the calyx terminal will measure vesicular glutamate release followed by 3D reconstruction of the calyx to quantify structural development. Patch clamp recordings of the MNTB neuron with afferent fiber stimulation will be done to measure glutamate-mediated currents, and immunohistochemistry will visualize glutamate receptors in the calyx synapse. Aim 3 tests auditory processing following PNE using in vivo auditory tests. The proposed aims will reveal cellular and circuit-level mechanisms underlying developmental nicotine exposure-induced auditory deficits that will be useful for future therapeutics.

项目概要产前接触香烟烟雾会增加婴儿猝死综合症的风险值得注意的是，大脑发育缺陷一直持续到成年。由于电子烟的日益普及，产前接触香烟后的听觉系统对产前接触尼古丁的研究变得越来越重要。审计鼠发育期发生在出生后，使得围产期尼古丁接触准确模型产前尼古丁暴露对听觉系统表型的影响在 PNE 模型中，谷氨酸能被破坏。据报道，听觉皮层的信号传导和听觉惊吓测试中的时间处理受损。然而，围产期尼古丁暴露（PNE）损害听觉发育的细胞机制和中枢听觉处理目前尚不清楚在听觉系统中，胆碱能信号是必需的。最近的工作证明了烟碱的重要性。乙酰胆碱受体在梯形体内侧核（MNTB）噪声信号检测中的作用听觉脑干。α7 烟碱乙酰胆碱受体 (α7 nAChR)，对于谷氨酸能突触至关重要。产后早期 MNTB 中高度表达利用 MNTB 的大型谷氨酸能花萼，拟议的研究旨在研究 PNE 对萼末端、MNTB 突触结构和功能发育的影响中枢听觉处理的中心假设是 PNE 增加 α7 nAChR 的表达及其慢性影响。激活会损害 MNTB 中的谷氨酸突触发育，导致中枢听觉缺陷。鉴于 MNTB 在双耳处理中的关键作用，研究 MNTB 如何受到 PNE 的影响非常重要在听觉发育过程中了解产前接触过的儿童的听觉处理障碍目标 1 检查花萼-MNTB 突触处 nAChR 的发育表达以及尼古丁的影响。使用膜片钳电生理学、免疫组织化学和蛋白质印迹研究 PNE 对 nAChR 表达的影响。图2研究了PNE对Held Direct突触花萼的结构和功能的发育影响。花萼末端的突触前记录将测量囊泡谷氨酸释放，然后进行 3D 重建花萼以定量 MNTB 神经元的结构发育。将进行传入纤维刺激以测量谷氨酸介导的电流，并且免疫组织化学将进行可视化花萼突触中的谷氨酸受体，Aim 3 使用体内 PNE 测试听觉处理。听觉测试的目标将揭示发育背后的细胞和电路水平机制。尼古丁暴露引起的听觉缺陷将有助于未来的治疗。