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

描述（由申请人提供）：发育性听力损失（HL）可引起听觉处理和认知过程（如语言习得）的深刻变化。这是因为中枢神经系统特别容易受到成年之前的离散间隔期间的感觉活动的干扰。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补救与正常功能的恢复高度相关。这表明关键期概念适用于人类听力损失。这一提议的核心假设是，从听力损失引起的皮层膜和突触特性变化中恢复取决于在一个或多个关键期关闭之前听力的恢复。该提案的主要目标是确定轻度听力损失（即，双边 耳塞），或恢复正常听力（即，耳塞移除）将影响听觉皮层中的细胞特性。耳塞插入的开始和耳塞移除的时间都将随着出生后年龄的变化而变化，以探索听觉CP的时间和终止。将在听觉皮层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。有两个实验目的。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CP，将使用双侧耳塞饲养动物，并改变EP插入的发病年龄。将从耳塞饲养和年龄匹配的未操作动物的丘脑皮质脑切片中的2/3层锥体神经元获得全细胞记录。电流钳记录将用于测量膜特性，电压钳记录将用于测量自发和诱发抑制性突触电流。这些措施将揭示是否有多个CP，在此期间，特定的皮质特性对听力损失敏感。目标2询问是否存在听力恢复允许细胞特性恢复的关键时期。因此，将用双侧EP饲养动物，并且在整个发育过程中，EP去除的年龄将不同。为了评价耳塞移除的影响，将在听力恢复的动物和年龄匹配的对照动物中获得全细胞记录。所有数据收集参数和分析方法将与目标1相同。实验将使我能够区分EP插入和移除的关键时期是否发生在相同的年龄窗口内，或者移除的关键时期是否取决于EP插入的年龄。总之，这些发现将揭示细胞特性成熟是否存在离散的关键时期，并表明发育性听力损失的补救是否存在最佳时期。

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.