Mechanisms of auditory cortex development and role of NMDA receptors

描述（申请人提供）：听觉皮层（AC）在处理复杂声音中起着至关重要的作用，由于出生后的经历，听觉皮层经历了重大的发育变化。早期听觉经验对前皮层的功能和结构具有深远和潜在的持久影响，并影响听觉感知和语言能力。以往的研究表明，在关键时期，持续暴露于中等水平的背景噪声中，没有任何频谱或时间结构，会延迟交流音质图的建立，损害频率选择性，造成交流发育迟缓（ACDD）。本课题旨在研究噪声诱导ACDD和AC发育的机制，揭示NMDA受体在AC发育和ACDD中的作用。为了实现这一目标，我将(1)使用长期植入电极监测正常发育和ACDD期间AC神经元的反应特性，(2)使用声惊吓反射的脉冲前抑制（PPI）来评估正常发育和ACDD期间的时间分辨率和频率辨别，以及(3)通过测量正常发育和ACDD期间mRNA和蛋白质水平来评估NMDA受体表达的变化。本文将探讨三个具体目标：(1)交流神经元在正常发育和ACDD期间发生了哪些功能变化？(2)时间分辨和频率分辨在正常发育和ACDD中是如何变化的？(3) NMDA受体在AC发育和ACDD中起什么作用？本提案中概述的行为实验将是第一个确定是否存在与ACDD相关的感知缺陷的实验。该研究也将首次评估NMDA受体在正常和异常AC发育中的作用。这些研究结果可能为改善儿童、失语症患者和人工耳蜗使用者的听觉记忆和学习缺陷的药物治疗提供新的见解。

DESCRIPTION (provided by applicant): The auditory cortex (AC) which plays a crucial role in processing complex sounds undergoes significant developmental changes as a result of postnatal experience. Early auditory experience can have a profound and potentially long lasting effect on the function and structure of the AC, and influence the hearing perception and language ability. Previous studies suggest that continuous exposure to moderate-level background noise without any spectral or temporal structure during the critical period delays the establishment of the tonotopic map of the AC and impairs frequency selectivity, creating AC developmental delay (ACDD). The goal of this proposal is to study the mechanism of AC development and noise induced ACDD, and to reveal the role of NMDA receptors in AC development and ACDD. To accomplish this goal, I will (1) use chronically implanted electrodes to monitor the response properties of neurons in AC during normal development and ACDD, (2) use pre-pulse inhibition (PPI) of the acoustic startle reflex to assess temporal resolution and frequency discrimination during normal development and ACDD, and (3) evaluate the change in NMDA receptor expression by measuring mRNA and protein levels during normal development and ACDD. Three specific aims will be addressed: (1) what functional changes occuring in AC neuron during the normal development and ACDD? (2) How does the temporal resolution and frequency discrimination change during the normal development and in ACDD? (3) what role do NMDA receptors play in AC development and ACDD? The behavioral experiments outlined in this proposal will be the first to determine if there are any perceptual deficits associated with the ACDD. The research will also be the first to evaluate the role of NMDA receptors in normal and abnormal AC development. The result of these studies may lead to new insights into pharmacologic therapies for improving auditory memory and learning deficits in children, aphasia patients and cochlear implant users.