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.

项目概要 即使是短暂的发育性听力损失（HL）也会导致听觉感知的持久缺陷，影响 许多儿童的言语和语言习得以及随后的教育程度。虽然研究 表明发育性 HL 会损害时间处理（例如幅度调制处理）， 有证据表明频谱内容感知的损害与语音密切相关 理解。此外，有证据表明，这些赤字部分是由于长期持续减少造成的。 听觉皮层（AC）抑制性突触的强度。因此，本提案的目标是评估 发育 HL 对沙鼠光谱调制 (SM) 检测任务的影响并确定因果关系 AC 中知觉缺陷与 GABAB 受体介导的抑制减少之间的关系。核心 该提案的假设是，发育性 HL 将导致突触后功能降低 GABAB 受体，从而损害光谱调制刺激的 AC 编码并导致 SM 检测 赤字。两个目标测试从该假设中得出的预测：目标 1A 将确定以下因素的影响： 检测到 SM 刺激时出现发育性听力损失。沙鼠将从 P11 开始使用双边耳塞饲养 23日，AC抑制尤其脆弱的时期。摘除耳塞十二天后，将对动物进行测试 SM检测任务。 SM阈值将在10天内获得，以便感知学习和 可以对对照动物和 HL 饲养动物的渐近表现进行比较。目标 1B 将决定 使用清醒行为准备，发育性 HL 是否会损害 SM 刺激的 AC 神经元编码。 AC 将植入电极阵列，并在 SM 任务执行期间获取记录。神经 将测量正常听力动物和 HL 动物对一系列调制深度的敏感性。目标2将 测试 AC 中功能性 GABAB 受体减少导致 SM 感知受损的预测 发展性HL。使用新型 AAV 载体表达沙鼠特异性 GABAB 受体亚基 (Gabrb1b) 从发育 HL 后最近测序的 AC 沙鼠基因组中获得。 AAV-Gabrb1b 载体 拔掉耳塞后，将双侧注入交流电中。然后将进行行为测试以确定 是否恢复正常的SM检测阈值。这些目标共同将增进我们对 发展性 HL 知觉缺陷背后的神经机制，并确定一条通往发展的道路 开发第一种药物治疗方法，以获得持久的效果。