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， 大脑中持续到成年的发育缺陷。已经观察到感官损伤，特别是 在听觉系统中的作用。由于电子烟的日益普及， 对产前单独暴露于尼古丁的研究的需要变得越来越重要。临界 小鼠听觉发育期发生在出生后，允许围产期尼古丁暴露准确地 模型产前尼古丁暴露对听觉系统表型的影响在PNE模型中， 已经报道了在听觉惊吓测试中听觉皮层中的信号传导和受损的时间处理。 然而，围产期尼古丁暴露（PNE）损害听觉发育的细胞机制 和中央听觉处理目前尚不清楚。在听觉系统中，胆碱能信号是必要的 用于外周和中枢听觉过程。最近的研究表明， 乙酰胆碱受体的信号在噪声检测中的内侧核的斜方体（MNTB）的 听觉脑干α 7烟碱型乙酰胆碱受体（α7 nAChR），是突触兴奋所必需的 在海马和皮质的发育中，在出生后早期在MNTB中高度表达 发展利用MNTB的Held突触的大的突触能萼，所提出的研究旨在 研究PNE对花萼末端、MNTB突触的结构和功能发育的影响， 中央听觉处理中心假设是PNE增加α7 nAChR表达， 激活损害MNTB中的神经元能突触发育，导致中枢听觉缺陷。由于 MNTB在双耳处理中的关键作用，重要的是要检查MNTB如何受到PNE的影响 在听觉发育过程中，了解产前暴露于 尼古丁。目的1检测nAChR在花萼-MNTB突触的发育表达以及 使用膜片钳电生理学、免疫组织化学和蛋白质印迹法观察PNE对nAChR表达的影响。目的 第二部分研究了PNE对Held突触萼结构和功能的发育影响。直接 突触前记录的花萼末端将测量囊泡谷氨酸释放，随后进行3D 重建花萼以量化结构发育。膜片钳记录的MNTB神经元与 将进行传入纤维刺激以测量谷氨酸介导的电流，免疫组织化学将 可以看到萼突触中的谷氨酸受体。目的3使用活体测试PNE后的听觉处理 听觉测试该研究旨在揭示发育过程中的细胞和回路水平的机制， 尼古丁成瘾引起的听觉缺陷，这将是有用的未来的治疗。