Activity-Dependent Influences on Auditory Circuits

描述（由申请人提供）：拟议研究的总体目标是更好地了解听觉体验退化对大脑功能的影响，这些变化发生的机制，以及这些知识如何有助于制定有效的补救策略。传导性听力损失（CHL）形式的听力退化，如渗出性中耳炎，是美国儿童中最常见的诊断疾病，并且反复与听觉感知过程缺陷相关，这种缺陷在传导性听力损失解决后持续数年。为了更好地理解这些持久的加工缺陷背后的机制，我们利用了一种可逆CHL技术，可以精确控制发育性听力损失的时间和双侧表达。提出的实验将CHL的历史与单个神经元反应特性的可塑性以及它们在功能图中的协调排列联系起来。初始实验将改变CHL发病年龄，以描绘下丘、内侧膝状体和初级听觉皮层双耳加工的敏感期调节。继续的研究将比较单侧和双侧CHL对中脑和前脑核功能组织的影响，并确定一旦恢复正常听力后，可塑性的持久方面与那些逐渐消失的方面。第二项研究将全面评估经验依赖对听觉皮层单耳和双耳刺激选择性的影响。这些研究将记录清醒动物的声谱、信噪比、时间包络变化以及单个神经元水平上的耳间水平和时间差异的编码可塑性。通过记录关键的“现实世界”变量，如CHL的时间、CHL的双侧模式和无CHL听力的长度对发育中的中央听觉系统的影响，这些研究进一步告知卫生保健从业者与各种儿童CHL干预策略相关的成本和收益。这些实验将进一步加深我们对经验如何塑造大脑功能和行为的理解。提出的工作将检查经验的指导作用，在形成大脑回路，调解双耳听力。通过将可逆性传导性听力损失方法与表征单个神经元水平可塑性的技术以及听觉中脑和前脑核的表征图相结合，本研究为解决经验依赖可塑性的基础研究问题和与儿童听力损失病理生理学相关的转化问题提供了一种有前途的方法。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to better understand the impact of degraded auditory experience on brain function, the mechanisms by which these changes occur, and how such knowledge can contribute to the development of effective remediation strategies. Degraded hearing in the form of conductive hearing loss (CHL) such as otitis media with effusion is the most commonly diagnosed illness among children in the United States and has been repeatedly associated with deficits in auditory perceptual processes that persist for years after the conductive loss has been resolved. To better understand the mechanisms underlying these enduring processing deficits, we have utilized a technique for reversible CHL that permits precise control over the timing and bilateral expression of developmental hearing loss. The proposed experiments will relate a history of CHL to plasticity of single neuron response properties and their coordinated arrangement into functional maps. Initial experiments will vary the age of CHL onset to delineate the sensitive period regulation of binaural processing in the inferior colliculus, medial geniculate body and primary auditory cortex. Continuing studies will compare the effects of unilateral versus bilateral CHL on the functional organization of midbrain and forebrain nuclei and identify the aspects of plasticity that endure versus those that fade away once normal hearing has been restored. A second line of research will provide a comprehensive assessment of experience-dependent influences on monaural and binaural stimulus selectivity in the auditory cortex. These studies will document plasticity in the encoding of sound spectra, signal-to-noise ratio, temporal envelope variations as well as interaural level and time differences at the level of the single neuron in the awake animal. By documenting how critical "real-world" variables such as the timing of CHL, the bilateral pattern of CHL and the length of CHL-free hearing impact the developing central auditory system, these studies further inform health care practitioners about the costs and benefits associated with various intervention strategies for childhood CHL. These experiments will further our understanding of how experience shapes brain function and behavior. The proposed work will examine the instructive role of experience in the formation of brain circuits that mediate binaural hearing. By combining a method for reversible conductive hearing loss with techniques to characterize plasticity at the level of single neurons and representational maps in auditory midbrain and forebrain nuclei, the proposed studies introduce a promising approach to address basic research questions regarding experience-dependent plasticity and translational questions related to the pathophysiology of childhood hearing loss.