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 即使是短暂的发育性听力损失（HL）也会导致听觉感知的持久缺陷， 语言和语言习得以及随后的教育成就。虽然研究 表明发育性HL可以损害时间处理（例如，幅度调制处理）， 这证明了对频谱内容感知的损害与语音密切相关 理解力此外，有证据表明，这些赤字的部分原因是， 听觉皮层抑制性突触的强度。因此，本提案的目标是评估 在沙鼠的光谱调制（SM）检测任务的发展HL的影响，并确定因果关系 AC中感知缺陷与GABAB受体介导的抑制减少之间的关系。核心 这一建议假设是，发育性HL将导致突触后神经元功能降低， GABAB受体，从而损害频谱调制刺激的AC编码并导致SM检测 赤字两个目标测试从这一假设中产生的预测：目标1A将决定 发展性听力损失的检测SM刺激。沙鼠将从P11开始用双侧耳塞饲养- 23，AC抑制特别脆弱的时候。在移除耳塞后12天，将对动物进行测试 一个SM检测任务。将在10天内获得SM阈值，以便感知学习和 可以在对照和HL饲养的动物之间比较渐近性能。目标1B将决定 是否发展HL损害AC神经元编码SM刺激使用觉醒行为准备。 AC将植入电极阵列，并在SM任务执行期间采集记录。神经 将在正常听力和HL动物之间测量对调制深度范围的敏感性。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， 发育性HL利用新型腺相关病毒载体表达沙鼠特异性GABAB受体亚基（Gabrb 1b） 从最近测序的沙鼠基因组中获得的发育HL后的AC。AAV-Gabrb 1b载体 将在耳塞取出后双侧注入AC。然后进行行为测试，以确定 是否恢复正常SM检测阈值。总之，这些目标将促进我们对 知觉缺陷的神经机制参与发展HL，并确定一条通往 开发出第一种药物治疗其持久的后果。