Genetic rescue of a developmental hearing loss-induced spectral processing deficit

发育性听力损失引起的频谱处理缺陷的基因拯救

• 批准号: 10537264
• 负责人: Samer Masri
• 金额: $ 6.76万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537264
• 关键词: Abbreviations; Acoustics; Address; Adolescent; Affect; Animal Model; Animals; Auditory Perception; Auditory area; Behavior; Behavioral; Behavioral Paradigm; Bilateral; Brain; Child; Code; Comprehension; Control Groups; Custom; Detection; Development; Discrimination; Ear; Earplug; Electrodes; Excision; Genetic; Genome; Gerbils; Goals; Impairment; Implant; Inhibitory Synapse; Language Development; Link; Measures; Mediating; Methods; Neurons; Noise; Perception; Perceptual learning; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Population; Preparation; Procedures; Process; Protein Isoforms; Reporter; Research; Role; Signal Transduction; Speech; Speech Perception; Stimulus; Task Performances; Testing; Therapeutic Intervention; Time; Training; Variant; Viral; Virus; Work; adeno-associated viral vector; aversive conditioning; awake; behavior test; calmodulin-dependent protein kinase II; critical period; deprivation; gene therapy; hearing impairment; hippocampal pyramidal neuron; neuromechanism; normal hearing; novel; novel therapeutics; postsynaptic; promoter; receptor; relating to nervous system; response; sound; speech in noise; support vector machine; synaptic inhibition; transmission process; vector

PROJECT SUMMARY Even transient developmental hearing loss (HL) can cause lasting deficits to auditory perception, affecting speech and language acquisition and subsequent educational attainment for many children. Although research suggests that developmental HL can impair temporal processing (e.g., amplitude modulation processing), there is evidence that impairments to the perception of the spectral content are closely correlated with speech comprehension. Furthermore, there is evidence that these deficits are due, in part, to a long-lasting reduction in the strength of inhibitory synapses in auditory cortex (AC). Therefore, the goals of this proposal are to assess the impact of developmental HL on a spectral modulation (SM) detection task in gerbils and to identify a causal relationship between perceptual deficits and reductions in GABAB receptor-mediated inhibition in AC. The core hypothesis of this proposal is that developmental HL will cause a reduction in the function of postsynaptic GABAB receptors, thereby impairing AC encoding of spectrally modulated stimuli and leading to SM detection deficits. Two aims test predictions emerging from this hypothesis: Aim 1A will determine the influence of developmental hearing loss on detection of SM stimuli. Gerbils will be reared with bilateral earplugs from P11- 23, a time when AC inhibition is particularly vulnerable. Twelve days after earplug removal, animals will be tested on a SM detection task. SM thresholds will be obtained across 10 days so that perceptual learning and asymptotic performance can be compared between control and HL-reared animals. Aim 1B will determine whether developmental HL impairs AC neuron encoding of SM stimuli using an awake-behaving preparation. AC will be implanted with an electrode array and recordings will be acquired during SM task performance. Neural sensitivity to a range of modulation depths will be measured between normal hearing and HL animals. Aim 2 will test the prediction that reduced functional GABAB receptors in AC contribute to impaired perception of SM after developmental HL. Using a novel AAV vector to express a gerbil-specific GABAB receptor subunit (Gabrb1b) obtained from the recently sequenced gerbil genome in AC after developmental HL. The AAV-Gabrb1b vector will be injected bilaterally into AC after earplug removal. Behavioral testing will then be performed to determine whether normal SM detection thresholds are restored. Together, these aims will advance our understanding of the neural mechanisms underlying perceptual deficits attending developmental HL and identify a path towards developing the first pharmaceutical treatments for its lasting consequences.

项目摘要 即使是短暂的发育听力损失（HL）也会导致听觉感知的持久赤字，从而影响 言语和语言获取以及随后的许多儿童的教育成就。虽然研究 表明发展性HL会损害时间处理（例如，幅度调制处理）， 证据表明对光谱含量感知的损害与语音密切相关 理解。此外，有证据表明这些赤字部分归因于持久的减少 听觉皮层（AC）中抑制突触的强度。因此，该提案的目标是评估 发育性HL对光谱调制（SM）检测任务的影响并确定因果关系 感知缺陷与AC中GABAB受体介导的抑制作用的减少之间的关系。核心 该提议的假设是发展性HL会导致突触后功能的降低 GABAB受体，从而损害了频谱调制刺激的AC编码并导致SM检测 缺陷。从这个假设中得出的两个目标测试预测：目标1a将决定 检测SM刺激的发育听力损失。沙鼠将用P11-的双侧耳塞饲养 23，AC抑制特别脆弱的时期。耳塞移除十二天后，将测试动物 在SM检测任务上。 SM阈值将在10天内获得，以便感知学习和 可以比较对照和HL饲养动物之间的渐近性能。 AIM 1B将确定 发育HL是否会使用醒着的做好准备损害SM刺激的AC神经元编码。 AC将用电极阵列植入，并在SM任务性能期间获取录制。神经 正常听力和HL动物之间将测量对一系列调制深度的敏感性。 AIM 2意志 测试以下预测，即AC中降低功能性GABAB受体有助于SM的感知受损 发展HL。使用新型的AAV矢量表达出沙鼠特异性GABAB受体亚基（GABRB1B） 从发育HL后AC中最近测序的Gerbil基因组获得。 AAV-GABRB1B矢量 移除耳塞后，将双侧注射到AC中。然后将执行行为测试以确定 是否恢复正常的SM检测阈值。这些目标在一起将提高我们对 参加发育HL的知觉缺陷的基础神经机制，并确定了通往的途径 为其持久后果开发第一个药物治疗方法。