Modulatory Circuits in the Auditory System

摘要 乙酰胆碱是一种神经递质，在听力的许多方面发挥作用，包括选择性注意， 学习、频率选择性、声音定位和语音辨别。它还扮演着一个关键的角色 在帮助大脑在正常发育、老化和对耳朵损伤做出反应方面的作用 或者中枢神经系统。自上而下的调制，其中较高级的大脑中枢改变早期的声音 加工，往往通过与胆碱能通路的相互作用，促成了其中的许多功能。一个 这项研究的长期目标是了解胆碱能输入如何调节脑干听觉处理。 以及来自听觉皮质的投射如何对这些功能做出贡献。本提案将涉及四个问题 我们知识中的主要空白限制了我们对听觉脑干胆碱能功能的了解。这个 我们知识的第一个缺口是缺乏关于大多数脑干听觉的胆碱能输入来源的信息 原子核。AIM 1将通过在新创造的转基因中使用最近开发的病毒载体来识别这些来源 老鼠。第二个缺口与单个胆碱能细胞的不同投射有关。其他细胞中的调制细胞 大脑区域通常有分支轴突，以便进行广泛的调制。AIM 2将使用多标签跟踪 转基因小鼠以识别可能支持同时调节大范围的 听觉脑干。第三个缺口是几乎完全缺乏有关胆碱能受体类型的信息。 有特殊的脑干回路。皮质下听觉系统中存在多种受体类型，这表明 各种短期和长期影响。目标3将把解剖道示踪和原位荧光结合起来 杂交(FISH)鉴定与特定上行通道相关的特定胆碱能受体成分 以及下行的听觉回路。我们知识中的第四个缺口与脑干的同一性有关 由听觉皮质的投射直接接触的胆碱能回路。AIM 4将使用 在转基因动物中使用常规示踪剂以及跨突触跨节病毒方法来测试 假设皮质投射与支配许多皮质下听觉核团的胆碱能细胞接触。 这些结果将确定负责皮质驱动释放的胆碱能回路。 乙酰胆碱。总体而言，四个目标的结果将提供有关脑干的基本信息 胆碱能回路，它们在听觉通路中的靶点，以及它们可能被激活的程度 来自高级大脑中心的投射。这些信息对于未来的设计和解释是必不可少的 了解胆碱能和自上而下调节以及深入了解治疗方法的实验 预防或治疗与这些系统功能障碍相关的缺陷。

Abstract Acetylcholine is a neurotransmitter that plays a role in many aspects of hearing, including selective attention, learning, frequency selectivity, sound localization, and discrimination of speech sounds. It also plays a critical role in helping the brain adapt during normal development, during aging and in response to damage of the ear or central nervous system. Top-down modulation, in which higher brain centers modify early acoustic processing, contributes to many of these functions, often through interactions with cholinergic pathways. A long-term goal of this research is to understand how cholinergic inputs modulate brainstem auditory processing and how projections from auditory cortex contribute to these functions. The present proposal will address four main gaps in our knowledge that limit our understanding of cholinergic function in the auditory brainstem. The first gap in our knowledge is lack of information on sources of cholinergic input to most brainstem auditory nuclei. Aim 1 will identify these sources by using recently developed viral vectors in newly created transgenic mice. A second gap concerns divergent projections from individual cholinergic cells. Modulatory cells in other brain areas typically have branching axons to allow widespread modulation. Aim 2 will use multi-label tracing in transgenic mice to identify divergent circuits that could support concurrent modulation of large expanses of the auditory brainstem. A third gap is a nearly total lack of information on cholinergic receptor types associated with specific brainstem circuits. Numerous receptor types occur in the subcortical auditory system, suggesting a variety of short- and long-term effects. Aim 3 will combine anatomical tract tracing with fluorescent in situ hybridization (FISH) to identify specific cholinergic receptor components associated with particular ascending and descending auditory circuits. The fourth gap in our knowledge concerns the identity of brainstem cholinergic circuits that are directly contacted by projections from the auditory cortex. Aim 4 will use conventional tracers as well as trans-synaptic intersectional viral methods in transgenic animals to test the hypothesis that cortical projections contact cholinergic cells that innervate many subcortical auditory nuclei. These results will identify the cholinergic circuits that are responsible for cortically-driven release of acetylcholine. Overall, the results from the four Aims will provide fundamental information about brainstem cholinergic circuits, their targets within the auditory pathway, and the extent to which they may be activated by projections from higher brain centers. This information is essential for the design and interpretation of future experiments to understand cholinergic and top-down modulation and for insight into therapeutic approaches to prevent or treat deficits associated with dysfunction of these systems.