权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10672208
负责人：
Samer Masri
金额：
$ 7.18万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
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/10672208
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 Education Electrodes Excision Genetic Genome Gerbils Goals Hearing Tests Impairment Implant Inhibitory Synapse Language Development Link Measures Mediating Methods Neurons Noise Perception Perceptual learning Performance Pharmacologic Substance 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 With laterality Work adeno-associated viral vector aversive conditioning awake behavior test calmodulin-dependent protein kinase II comparison control critical period deprivation drug action gene therapy hearing impairment hippocampal pyramidal neuron neural neuromechanism normal hearing novel novel therapeutics pharmacologic postsynaptic promoter receptor response sound speech in noise support vector machine synaptic inhibition transmission process vector

项目摘要

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.

项目总结