Modulatory Circuits in the Auditory System

 描述（由申请人提供）：乙酰胆碱是一种神经递质，在听觉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。它还在帮助麸皮适应正常发育，衰老以及对耳朵或中枢神经系统损伤的反应中起着关键作用。这项研究的长期目标是了解胆碱能输入脑干听觉回路有助于这些任务。最近的研究已经确定了4种不同的胆碱能系统，支配脑干听觉通路。这些胆碱能系统具有不同的功能，例如唤醒、设置神经元敏感性或控制听觉信息的流动（例如，以确定声刺激是否被有意识地感知）。了解脑干胆碱能功能的一个主要障碍是缺乏关于哪些胆碱能来源与哪些听觉通路联系的信息。这个提议的目的是确定脑干听觉回路是特定的脑干胆碱能投射系统的主要目标。实验将使用最近开发的病毒载体和基因工程（“转基因”）大鼠标记来自已确定来源的胆碱能回路。这些技术将结合多标记的解剖示踪剂和免疫化学，以确定胆碱能系统针对特定的听觉回路的组件和突触组织。目的集中在两个脑干区域，表现出高水平的胆碱能神经支配：腹侧耳蜗核（VCN）和下丘（IC）。这两个区域共同处理几乎所有的听觉信息，从而对听觉功能的各个方面做出贡献。目标1将专注于VCN，这是一个从耳朵直接接收输入并产生通往更高中心的多条通路的区域。这些实验将确定特定上行通路的胆碱能输入。目标2和3将集中在IC，最大的脑干听觉中心和听觉信息整合的主要枢纽。目标2将确定特定的细胞类型的IC胆碱能输入的目标。目的3将确定IC内的回路，这些回路可能受到胆碱能输入的调制， 控制听觉信息在这个整合中心的处理方式。总的来说， 这三个目标将通过为设计和解释未来的光遗传学，生理学和行为实验提供必要的信息来推动该领域的发展，以更好地了解胆碱能在正常听力，发育，学习和衰老以及耳蜗或中枢听觉系统损伤后的作用。

 DESCRIPTION (provided by applicant): 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 bran adapt during normal development, during aging and in response to damage of the ear or central nervous system. The long term goal of this research is to understand how cholinergic inputs to brainstem auditory circuits contribute to these tasks. Recent studies have identified 4 different cholinergic systems that innervate the brainstem auditory pathways. These cholinergic systems have different functions such as arousal, setting neuronal sensitivity, or controlling the flow of auditory information (e.g., to determine whether an acoustic stimulus is consciously perceived). A major obstacle to understand cholinergic functions in the brainstem has been lack of information about which cholinergic sources contact which auditory pathways. The objective of this proposal is to identify brainstem auditory circuits that are major targets of specific brainstm cholinergic projection systems. The experiments will use recently developed viral vectors and genetically-engineered ("transgenic") rats to label cholinergic circuits from identified sources. These techniques will be combined with multi-labeling anatomical tracers and immunochemistry to identify the components and synaptic organization of specific auditory circuits targeted by the cholinergic systems. The Aims focus on two brainstem areas that show high levels of cholinergic innervation: the ventral cochlear nucleus (VCN) and the inferior colliculus (IC). Together, these 2 areas process nearly all auditory information and thus contribute to all aspects of auditory function. Aim 1 will focus on the VCN, a region that receives direct input from the ear and that gives rise to multiple pathways to higher centers. The experiments will identify cholinergic inputs to specific ascending pathways. Aims 2 and 3 will focus on the IC, the largest brainstem auditory center and a major hub for integration of auditory information. Aim 2 will identify specific cell types in the IC that are targeted by cholinergic inputs. Aim 3 will idetify the circuits within the IC that are likely to be modulated by the cholinergic inputs and that could control how auditory information is processed within this integrative center. Overall, results from the three Aims will move the field forward by providing essential information for designing and interpreting future experiments with optogenetics, physiology and behavior to better understand cholinergic roles in normal hearing, during development, learning and aging and after damage to the cochlea or central auditory system.