Modulatory Circuits in the Auditory System

听觉系统中的调制电路

• 批准号: 10491180
• 负责人: Brett R Schofield
• 金额: $ 59.34万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491180
• 关键词: Acetylcholine; Acoustics; Address; Aging; Anatomy; Area; Arousal; Auditory; Auditory area; Auditory system; Axon; Brain; Brain Stem; Cavia; Cell Nucleus; Cells; Cholinergic Receptors; Cochlea; Cochlear Implants; Cochlear nucleus; Complex; Data; Development; Disease; Ear; Environment; Fluorescent in Situ Hybridization; Frequencies; Functional disorder; Future; Goals; Grant; Hearing; Individual; Inferior Colliculus; Knowledge; Label; Learning; Left; Long-Term Effects; Mediating; Methods; Midbrain structure; Muscarinic Acetylcholine Receptor; Nervous system structure; Neuraxis; Neurotransmitters; Nicotinic Receptors; Pathway interactions; Pattern; Perception; Persons; Physiological; Play; Population; Presbycusis; Research; Rewards; Role; Schizophrenia; Sleep Wake Cycle; Sound Localization; Source; Speech; Speech Discrimination; Speech Sound; Synapses; System; Tegmentum Mesencephali; Testing; Thalamic structure; Therapeutic; Tracer; Transgenic Animals; Transgenic Mice; Viral; Viral Vector; auditory feedback; auditory nuclei; auditory pathway; auditory processing; autism spectrum disorder; cell type; cholinergic; coping; design; experimental study; hearing impairment; insight; nerve supply; neuronal excitability; normal hearing; prevent; receptor; response; selective attention; sensory gating

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.

抽象的 乙酰胆碱是一种神经递质，在听力的许多方面发挥作用，包括选择性注意力、 学习、频率选择性、声音定位和语音辨别。也起到了至关重要的作用 在帮助大脑适应正常发育、衰老和耳朵损伤过程中的作用 或中枢神经系统。自上而下的调制，其中较高级的大脑中心修改早期的声学 通常通过与胆碱能途径的相互作用来促进其中许多功能。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 以及听觉皮层的投射如何促进这些功能。本提案将解决四个问题 我们知识中的主要差距限制了我们对听觉脑干胆碱能功能的理解。这 我们知识中的第一个差距是缺乏有关大多数脑干听觉的胆碱能输入来源的信息 原子核。目标 1 将通过在新创建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。第二个差距涉及单个胆碱能细胞的不同预测。其他调节细胞 大脑区域通常具有分支轴突以允许广泛的调节。目标 2 将使用多标签追踪 转基因小鼠识别出可以支持大范围同时调节的发散电路 听觉脑干。第三个差距是几乎完全缺乏相关胆碱能受体类型的信息。 具有特定的脑干回路。皮层下听觉系统中存在多种受体类型，表明 各种短期和长期影响。目标 3 将解剖束追踪与原位荧光相结合 杂交（FISH）以识别与特定上行相关的特定胆碱能受体成分 和下行听觉回路。我们知识中的第四个缺口涉及脑干的身份 胆碱能回路与听觉皮层的投射直接接触。目标4将使用 传统示踪剂以及转基因动物中的跨突触交叉病毒方法来测试 假设皮质投射接触支配许多皮质下听觉核的胆碱能细胞。 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，它们在听觉通路内的目标，以及它们可能被激活的程度 来自高级大脑中心的预测。这些信息对于未来的设计和解释至关重要 通过实验了解胆碱能和自上而下的调节，并深入了解胆碱能的治疗方法 预防或治疗与这些系统功能障碍相关的缺陷。