AFFERENT INFLUENCES ON AUDITORY SYSTEM ONTOGENY

理解正常和异常大脑发育的基本原理需要了解细胞事件，即不同的经验影响神经结构和功能的个体发生。在听觉系统中，随着人工耳蜗在先天性和语前听力受损婴儿中越来越多的使用，这一研究领域已经取得了新的和直接的临床重要性。本申请寻求继续资助一个研究项目，旨在了解内耳完整性和活动对脑干听觉通路发育影响的细胞事件。将继续或展开四项不同的调查。1. 我们将继续研究细胞内钙稳态在幼龄动物内耳损伤或内耳活动剥夺导致脑干神经元跨神经元细胞死亡的事件开始调控中起关键作用的假设。2. 我们将研究一个特定分子的活动依赖性调节，一个钾通道（Kv1.1），被认为在听觉信息的时间编码中起着独特的重要作用。该分子表达的传入调控将在耳蜗核细胞的基因转录、蛋白质和功能特性水平上进行研究。3. 我们将使用正常和突变小鼠来研究发育和成熟大脑对剥夺性变性的不同易感性的生物学原理。4. 我们将结合单细胞标记、电生理学和钙成像等方法，研究树突结构传入调控的细胞机制。

Understanding the fundamental principles of normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. In the auditory system, this area of research has achieved new and immediate clinical importance with the increasing use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events underlying the influence of inner ear integrity and activity on development of brainstem auditory pathways. Four separate lines of investigation will be either continued or initiated. 1. We will continue to investigate the hypothesis that intracellular calcium homeostasis plays a key role in regulating the initiation of events leading to transneuronal cell death of brainstem neurons in young animals following damage to the inner ear or deprivation of acoustically driven inner ear activity. 2. We will investigate activity-dependent regulation of a specific molecule, a potassium channel (Kv1.1), thought to play a uniquely important role in the temporal coding of auditory information. Afferent regulation of the expression of this molecule will be examined at the levels of gene transcription, protein, and functional properties of cochlear nucleus cells. 3. We will use normal and mutant mice to examine the biological principles underlying differential susceptibility of the developing and mature brains to deprivation-induced degeneration. 4. We will combine single cell labeling, electrophysiology and calcium imaging methods to study the cellular mechanisms of afferent regulation of dendritic structure.