Critical Periods of Recovery from Hearing Loss in the Developing Auditory Cortex

描述(申请人提供)：发育性听力损失(HL)可导致听觉处理和认知过程的深刻变化，如语言习得。这是因为在成年期之前，中枢神经系统特别容易受到感觉活动中断的影响。这些间隔通常被称为关键期(CP)。与基础研究结果一致，人类听力损失的早期修复与正常功能的恢复高度相关。这表明临界期的概念适用于人类听力损失。这一建议的核心假设是，从听力损失引起的皮质膜和突触特性的变化中恢复取决于一个或多个关键期关闭之前听力的恢复。这项建议的主要目标是确定在轻度听力损失(即双侧听力损失)期间的CPS 耳塞)，或在发育过程中恢复正常听力(即拔掉耳塞)将影响听觉皮质的细胞特性。耳塞插入的开始时间和拔除耳塞的时间都将随着出生后年龄的不同而变化，以探讨听性CPS的时机和终止。将在听觉皮质中评估有助于神经元兴奋性的两个关键细胞特性：(1)膜和放电特性，以及(2)抑制性突触电流。有两个实验目标。目标1询问是否存在一个以上的CP，在此期间听力损失影响细胞特性。为了确定是否存在轻度听力损失的CPS，动物将使用双侧耳塞饲养，植入EP的起效年龄将有所不同。全细胞记录将从耳塞饲养和年龄匹配的未经操作的动物的丘脑皮质脑片中的第2/3层锥体神经元获得。电流钳记录将被用来测量膜特性，电压钳记录将被用来测量自发和诱发的抑制性突触电流。这些测量将揭示是否存在多个CP，在此期间特定的皮质特性对听力损失敏感。目标2询问是否存在一个关键时期，在此期间听力恢复允许细胞特性的恢复。因此，动物将用双侧EP饲养，EP移除的年龄在整个发育过程中会有所不同。为了评估摘除耳塞的效果，将获得听力恢复的动物和年龄匹配的对照组动物的全细胞录音。所有数据收集参数和分析方法将与目标1相同。该实验将使我能够区分EP插入和取出的临界期是否出现在同一年龄窗口内，或者EP插入的临界期是否取决于EP插入的年龄。综上所述，这些发现将揭示是否存在细胞特性成熟的离散关键期，并暗示是否存在修复发育性听力损失的最佳时期。

DESCRIPTION (provided by applicant): Developmental hearing loss (HL) can induce profound changes to auditory processing and cognitive processes, such as language acquisition. This is because the central nervous system is particularly vulnerable to disruptions of sensory activity during discrete intervals prior to adulthood. These intervals are often referre to as critical periods (CP). Consistent with basic research findings, early remediation of hearing loss in humans is highly correlated with recovery of normal function. This suggests that the critical period concept applies to human hearing loss. The core hypothesis of this proposal is that recovery from hearing loss-induced changes to cortical membrane and synaptic properties depends on the restoration of hearing prior to the closure of one or more critical periods. The key goals of this proposal are to determine the CPs during which mild hearing loss (i.e., bilateral earplugs), or the restoration of normal hearing (i.e., earplug removal) during development will influence cellular properties in auditory cortex. Both the onset of earplug insertion and the time of earplug removal will be varied as a function of postnatal age to explore the timing and termination of auditory CPs. Two key cellular properties that contribute to neuronal excitability will be assessed in the auditory cortex: (1) Membrane and firing properties, and (2) Inhibitory synaptic currents. There are two experimental Aims. Aim 1 asks whether there is more than one CP during which hearing loss affects cellular properties. To determine whether there are CPs for mild hearing loss, animals will be reared with bilateral earplugs and the age-of-onset for EP insertion will be varied. Whole-cell recordings will be obtained from layer 2/3 pyramidal neurons in thalamocortical brain slices from earplug-reared and age-matched unmanipulated animals. Current-clamp recordings will be used to measure membrane properties and voltage-clamp recordings will be used to measure spontaneous and evoked inhibitory synaptic currents. These measures will reveal whether there are multiple CPs during which specific cortical properties are sensitive to hearing loss. Aim 2 asks whether there is a critical period during which hearing restoration permits recovery of cellular properties. Therefore, animals will be reared with bilateral EPs and the age of EP removal will be varied throughout development. To evaluate the effects of earplug removal, whole cell recordings will be obtained in animals with restored hearing and age- matched controls. All data collection parameters and analytical approaches will be identical to Aim 1. The experiment will allow me to distinguish whether the critical period for EP insertion and removal occur within the same age window, or whether the critical periods for removal depend on the age of EP insertion. Together, these findings will reveal whether there are discrete critical periods for the maturation of cellular properties, and suggest whether there are optimal periods for remediation of developmental hearing loss.