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

• 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
• 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

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.

项目摘要 产前暴露于香烟烟雾会增加婴儿猝死综合症的风险 发展性在大脑中持续到成年。感官障碍已被观察到 在听觉系统中，产前卷烟暴露。由于电子烟的流行越来越高， 仅针对产前暴露于尼古丁的研究的需求变得越来越重要。关键 小鼠听觉发育的时期发生在出生后，可以准确暴露于围产期尼古丁 在听觉系统表型上模型产前尼古丁暴露。在PNE模型中，破坏了谷氨酸能 在听觉皮层中的信号传导和听觉惊吓测试中的临时处理受损。 但是，围产期尼古丁暴露（PNE）的细胞机制会损害听觉的发展 目前未知中央听觉处理。在听觉系统中，需要胆碱能信号传导 用于外围和中央听觉过程。最近的工作证明了烟碱的重要性 乙酰胆碱受体在信号内检测中的乙酰胆碱核中梯形体（MNTB）的核中的受体 听觉脑干。 Alpha 7烟碱乙酰胆碱受体（α7NACHR），对于谷氨酸能突触必不可少 海马和皮质的发育在产后早期的MNTB中高度表达 发展。利用MNTB持有突触的大型谷氨酸乳头钙化，拟议的研究旨在 研究PNE对花萼末端，MNTB突触的结构和功能发展的影响 中央听觉处理。中心假设是PNE增加了α7NACHR表达及其慢性 激活会损害MNTB中谷氨酸能突触的发展，导致中央听觉缺陷。由于 MNTB在双耳加工中的关键作用，重要的是检查MNTB如何受到PNE的影响 在听觉开发期间，以了解产前暴露于儿童的听觉处理障碍 尼古丁。 AIM 1检查了NACHRS在Calyx-MntB突触中的发育表达以及 PNE使用Patch-Clamp电生理学，免疫组织化学和Western印迹对NACHR表达。目的 2研究了pne对固定突触的花萼的结构和功能的发育影响。直接的 花萼末端的突触前记录将测量囊泡谷氨酸释放，然后测量3D 花萼重建以量化结构发展。 MNTB神经元的斑块夹录制 将进行传入纤维刺激以测量谷氨酸介导的电流，并将免疫组织化学 可视化花萼突触中的谷氨酸受体。 AIM 3测试使用体内PNE后PNE处理后的听觉处理 听觉测试。提出的目标将揭示发育发展的基础机制和电路级机制 尼古丁暴露引起的听觉定义了对将来治疗有用的。