Heterogeneity of feed-forward inhibition in the dorsal cochlear nucleus

耳蜗背核前馈抑制的异质性

• 批准号: 7842474
• 负责人: Sidney P Kuo
• 金额: $ 4.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2012-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842474
• 关键词: Accounting; Acoustic Nerve; Acoustics; Address; Affect; Auditory; Auditory system; Barbiturates; Behavior; Brain; Brain Stem; Cell physiology; Cells; Characteristics; Complex; Cues; Disease; Ear; Engineering; Fluorescence; Functional disorder; Goals; Green Fluorescent Proteins; Hearing; Heterogeneity; Knowledge; Location; Mediating; Membrane; Modeling; Mus; Nerve; Nerve Fibers; Neurons; Noise; Patch-Clamp Techniques; Pattern; Phenotype; Preparation; Process; Property; Recruitment Activity; Resolution; Role; Shapes; Slice; Source; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic Intervention; Tinnitus; Transgenic Mice; Whole-Cell Recordings; age related; barbituric acid salt; base; dorsal cochlear nucleus; enhanced green fluorescent protein; extracellular; feeding; gamma-Aminobutyric Acid; in vivo; inhibitory neuron; insight; patch clamp; postsynaptic; public health relevance; reconstruction; research study; response; sound; transmission process; voltage clamp

DESCRIPTION (provided by applicant): Neuronal circuits in the auditory brainstem are specialized to extract and represent specific aspects of acoustic information. Inhibitory neurons feature prominently in these circuits, but how inhibition contributes to auditory processing is not well understood. The mammalian dorsal cochlear nucleus (DCN), one of the principal targets of auditory nerve fibers, is thought to process monaural cues used to localize sound sources. Feed-forward inhibition onto DCN principal cells from glycinergic neurons known as vertical cells is believed to contribute importantly to this function, yet the specific mechanisms that determine how activity in vertical cells is recruited and what effect these neurons have on their targets have not previously been identified. The objective of this proposal is to clarify the role of vertical cells in the DCN by directly investigating their cellular and synaptic properties. Whole-cell patch-clamp techniques, in combination with anatomical and immunohistochemical analysis, will be used to test the hypothesis that at least two functionally distinct subtypes of vertical cells account for the in vivo behavior of DCN principal neurons. To target recordings of vertical cells in a brainstem slice preparation, this study will take advantage of recently developed transgenic mice in which glycinergic neurons express green fluorescent protein. In Specific Aim 1, vertical cells will be categorized into different functional subtypes using electrophysiological and anatomical criteria. Specific Aim 2 will address the hypothesis that activity in vertical cell subclasses is differentially modulated by inhibition mediated by gamma-aminobutyric acid. Experiments in Specific Aim 3 will use dual whole-cell patch-clamp recordings between synaptically connected pairs of vertical cells and principal neurons to investigate whether subtype-specific inhibitory input from vertical cells contributes to the characteristic response properties of DCN principal cells. Successful completion of these aims will provide insight into the basic mechanisms underlying DCN function and may reveal previously unappreciated heterogeneity of vertical cell-mediated inhibition within the DCN. Public Health Relevance: Some forms of tinnitus (persistent ringing in the ears) are thought to arise from noise-induced or aging-related loss of vertical cell activity. Understanding the basic mechanisms underlying normal vertical cell function should provide insight into how loss of activity in these neurons may contribute to the pathophysiology of tinnitus and could suggest avenues for therapeutic intervention.

描述（由申请人提供）：听觉脑干中的神经元回路专门用于提取和表示声学信息的特定方面。抑制性神经元在这些回路中表现突出，但抑制性神经元如何促进听觉处理还不清楚。哺乳动物耳蜗背核（DCN）是听觉神经纤维的主要靶区之一，被认为处理用于定位声源的单耳线索。被称为垂直细胞的甘氨酸能神经元对DCN主细胞的前馈抑制被认为对该功能有重要贡献，但确定垂直细胞中的活性如何被招募以及这些神经元对其靶点有什么影响的具体机制以前尚未确定。本研究的目的是通过直接研究垂直细胞的细胞和突触特性来阐明垂直细胞在DCN中的作用。全细胞膜片钳技术，结合解剖和免疫组化分析，将被用来测试的假设，至少有两个功能不同的亚型的垂直细胞占DCN主要神经元的体内行为。为了在脑干切片制备中靶向记录垂直细胞，本研究将利用最近开发的转基因小鼠，其中甘氨酸能神经元表达绿色荧光蛋白。在特定目标1中，垂直细胞将使用电生理学和解剖学标准分类为不同的功能亚型。具体目标2将解决以下假设：垂直细胞亚类中的活性通过γ-氨基丁酸介导的抑制进行差异调节。具体目标3中的实验将使用突触连接的垂直细胞和主神经元对之间的双全细胞膜片钳记录来研究垂直细胞的亚型特异性抑制性输入是否有助于DCN主细胞的特征性反应特性。这些目标的成功完成将提供深入了解DCN功能的基本机制，并可能揭示DCN内垂直细胞介导的抑制的以前未被认识到的异质性。 公共卫生相关性：某些形式的耳鸣（耳朵中持续的铃声）被认为是由噪音引起的或与衰老相关的垂直细胞活动丧失引起的。了解正常垂直细胞功能的基本机制应该提供洞察如何在这些神经元的活动损失可能有助于耳鸣的病理生理学，并可能建议治疗干预的途径。