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

项目总结 即使是短暂的发育性听力损失(HL)也会导致永久性的听觉障碍，影响 许多儿童的言语和语言习得以及随后的教育成就。虽然研究 提示发育性HL可以损害时间加工(例如，幅度调制加工)，在那里 是否有证据表明光谱内容知觉的损害与言语密切相关 理解。此外，有证据表明，这些赤字在一定程度上是由于 听觉皮质抑制性突触的强度。因此，这项提案的目标是评估 发育中的HL对沙土鼠光谱调制(SM)检测任务的影响及其原因的确定 AC中知觉缺陷与GABAB受体介导的抑制减少之间的关系。其核心是 这一理论的假设是发育性HL会导致突触后功能的降低 GABAB受体，从而损害对光谱调制刺激的AC编码，并导致SM检测 赤字。两个目标测试了从这个假设中产生的预测：目标1A将决定 检测到SM刺激后的发育性听力损失。从P11开始，沙土鼠将用双侧耳塞饲养- 23岁，这是AC抑制特别脆弱的时候。摘除耳塞12天后，动物将接受测试 执行SM检测任务。SM阈值将在10天内获得，以便知觉学习和 在对照和HL饲养的动物之间可以比较渐近性能。目标1B将决定 发育性HL是否使用清醒行为准备来损害编码SM刺激的AC神经元。 交流将植入一个电极阵列，并将在SM任务执行期间采集记录。神经 对一系列调制深度的敏感性将在正常听力和HL动物之间进行测量。目标2将 验证AC中功能性GABAB受体减少与SM感觉受损有关的预测 发育性HL。利用新型AAV载体表达沙土鼠特异性GABAB受体亚单位(Gabrb1b) 从最近测序的沙土鼠基因组中获得了发育的HL后AC的基因组。AAV-Gabrb1b载体 在摘除耳塞后，将双侧注入AC。然后将进行行为测试，以确定 是否恢复正常的SM检测阈值。综合起来，这些目标将促进我们对 参与发育性HL的知觉缺陷的神经机制并确定一条通往 为其持久的后果开发第一种药物治疗方法。

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.