The Auditory Phenotype of Kv Channel Gene Mutations

Kv通道基因突变的听觉表型

• 批准号: 8013586
• 负责人: Daniel B. Polley
• 金额: $ 15.05万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013586
• 关键词: Acoustics; Action Potentials; Animals; Auditory; Auditory system; Behavior; Behavioral; Behavioral Assay; Biochemistry; Biophysics; Brain; Brain Stem; Cell Nucleus; Cell membrane; Cells; Characteristics; Detection; Discrimination; Exhibits; Frequencies; Gene Deletion; Gene Mutation; Generations; Genetic; Genotype; Goals; Grant; Hearing; Impairment; In Vitro; Inferior Colliculus; Knock-out; Knockout Mice; Light; Measurement; Measures; Membrane Potentials; Midbrain structure; Molecular; Mus; Mutation; Neurons; Pattern; Perception; Phenotype; Physiological; Play; Potassium; Probability; Process; Property; Protocols documentation; Rest; Role; Series; Shapes; Specificity; Stimulus; Structure; Testing; Variant; Wild Type Mouse; Work; audiogenic seizure; auditory stimulus; awake; behavioral impairment; computerized data processing; improved; information processing; neuronal excitability; neurophysiology; operation; receptive field; research study; response; sound; sound frequency; voltage

DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to understand how the intrinsic electrical excitability of neurons in central auditory system contributes to auditory signal processing. The type and amount of voltage- gated potassium (Kv) channels expressed in the cell membrane determine the shape, probability and temporal patterning of action potentials and therefore principally determine a neuron's intrinsic electrical excitability. Detailed analyses of Kv channel biochemistry and biophysics indicate that two Kv channels, Kv3.1 and Kv1.3, exhibit properties that are particularly germane to the aims of this proposal. Kv1.3 and Kv3.1 have been observed to have significant - and often opposing - roles in regulating the neuronal response threshold, maximum sustained firing rate and maximum following rate. Alterations in these response features have clear implications for acoustic signal processing, which will be explored in depth through the combined use of neurophysiological and behavioral assays in Kv3.1 and Kv1.3 knockout mice. Aim 1 seeks to characterize the effects of Kv3.1 and Kv1.3 deletion at the level of the single unit within the inferior colliculus (IC). Neurophysiological selectivity for variations in sound frequency, temporal envelope properties, intensity and binaural interaction will be compared in awake Kv3.1 null, Kv1.3 null and wild-type mice. Aim 2 would relate variations in neurophysiological responses to commensurate shifts in hearing thresholds. These experiments will implement a conditioned avoidance protocol to measure detection and discrimination thresholds for variations in sound frequency, temporal structure and intensity. Through the combined application of genetic, neurophysiological and behavioral analyses, the proposed experiments would further our understanding of how the basic building blocks of excitability in the brain impact auditory processing and perception. Relevance: These experiments will further our understanding of the molecular determinants of brain function and behavior. By studying the effects of single gene deletions on the physiological response properties of single cells in the brain and the hearing abilities of animals actively engaged in listening tasks, the proposed experiments may allow us to frame the effects of genetic mutations in a more integrative context of auditory system function. Furthermore, the proposed experiments could shed additional light on the role of intrinsic neuronal excitability in the context of auditory information processing as well as pathological states such as audiogenic seizure.

描述（由申请人提供）：所提议工作的长期目标是了解中枢听觉系统中神经元的固有电兴奋性如何有助于听觉信号处理。细胞膜中表达的电压门控钾 (Kv) 通道的类型和数量决定了动作电位的形状、概率和时间模式，因此主要决定了神经元的内在电兴奋性。 Kv 通道生物化学和生物物理学的详细分析表明，两个 Kv 通道 Kv3.1 和 Kv1.3 表现出与本提案的目标特别密切的特性。据观察，Kv1.3 和 Kv3.1 在调节神经元反应阈值、最大持续放电率和最大跟随率方面具有显着且通常相反的作用。这些反应特征的改变对声信号处理具有明显的影响，将通过在 Kv3.1 和 Kv1.3 敲除小鼠中结合使用神经生理学和行为测定来深入探索。目标 1 旨在描述 Kv3.1 和 Kv1.3 缺失在下丘 (IC) 内单个单元水平上的影响。将在清醒的 Kv3.1 null、Kv1.3 null 和野生型小鼠中比较声音频率、时间包络特性、强度和双耳相互作用变化的神经生理学选择性。目标 2 将神经生理反应的变化与听力阈值的相应变化联系起来。这些实验将实施条件回避协议来测量声音频率、时间结构和强度变化的检测和辨别阈值。通过遗传、神经生理学和行为分析的结合应用，所提出的实验将进一步了解大脑兴奋性的基本组成部分如何影响听觉处理和感知。 相关性：这些实验将进一步加深我们对大脑功能和行为的分子决定因素的理解。通过研究单基因缺失对大脑中单细胞的生理反应特性以及积极参与听力任务的动物的听力能力的影响，所提出的实验可能使我们能够在更综合的背景下构建基因突变的影响听觉系统功能。此外，所提出的实验可以进一步阐明内在神经元兴奋性在听觉信息处理以及听源性癫痫等病理状态中的作用。