Coding in Auditory Neurons: Effects of Amino Acids

听觉神经元的编码：氨基酸的作用

• 批准号: 8305089
• 负责人: Donald M. Caspary
• 金额: $ 26.94万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305089
• 关键词: Acoustics; Address; Adult; Affect; Age-Years; Aging; Amino Acid Neurotransmitters; Amino Acids; Animal Model; Animals; Area; Attention; Attenuated; Auditory; Auditory area; Auditory system; Autoradiography; Binding; Brain; Cell Nucleus; Chemical Exposure; Code; Complex; Deafferentation procedure; Dependence; Detection; Development; Disease; Elderly; Electrodes; Electrophysiology (science); Environment; Frequencies; Grant; Hair Cells; Human; Impairment; Implant; In Situ Hybridization; Individual; Labyrinth; Lesion; Link; Location; Maps; Measures; Medial geniculate body; Mediating; Modeling; Molecular; Nature; Neuraxis; Neurons; Neurotransmitters; Noise; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Physiology; Plastics; Population; Presbycusis; Process; Property; Protein Subunits; Psychoacoustics; Rattus; Research Design; Role; Sensory; Shapes; Signal Transduction; Silicon; Societies; Sorting - Cell Movement; Speech; Stimulus; Structure; Synapses; Techniques; Thalamic Nuclei; Thalamic structure; Trauma; Uncertainty; Western Blotting; Wood material; age related; aged; auditory pathway; base; brain cell; dorsal cochlear nucleus; gamma-Aminobutyric Acid; hearing impairment; immunocytochemistry; improved; neurochemistry; neurotransmission; novel; public health relevance; receptor; receptor binding; relating to nervous system; response; response marker; sound; speech processing; young adult

DESCRIPTION (provided by applicant): Age-related hearing loss is a complex disorder affecting 30% of the US population aged 65 to 74 years, and 50% of the population over 75 years of age and older. Psychoacoustic studies in young and elderly subjects with similar thresholds show age-related decrements in temporal processing and speech understanding in noise. This suggests that seniors have difficulty attending to and comprehending speech in a public setting leading to a tendency to withdraw from society. The proposed studies are based on the underlying hypothesis which suggests that age-related hearing loss is, in part, a maladaptive plastic response to a slow progressive deafferentation at the auditory periphery. In many species, sound exposure, chemical or physical peripheral trauma alters physiologic responses and markers of adult inhibitory neurotransmission at multiple levels of the auditory pathway. Subcortical temporal coding studies suggest that inhibitory circuits: Allow neural responses to accurately follow the envelope/temporal fine structure of complex acoustic signals; Are involved in gain control; Are likely to provide the adaptive substrate for novelty detection (Yu et al., 2009). Studies completed during the previous grant period have shown that inhibitory neurotransmitters are critically involved in preserving temporal and spectral fidelity of coded complex acoustic signals as these signals ascend the auditory pathway. These studies found significant age-related changes in GABA- and glycinergic inhibitory pharmacology and physiology in the dorsal cochlear nucleus and primary auditory cortex. Proposal studies will examine the nature of GABAA receptors (GABAARs) at the level of the medial geniculate body (MGB) in the context of aging. The auditory thalamic nucleus receives lemniscal and extralemniscal ascending inputs as well as reticular, limbic and descending inputs from auditory and nonauditory cortices. Proposed studies seek to characterize the unique makeup of GABAAR in MGB and their functional involvement in attention/novelty detection and temporal processing. Proposed studies will examine age-related changes in the role of the inhibitory neurotransmitter GABA in the MGB. Preliminary iontophoretic, receptor binding and measures of GABAA subunit protein suggest an important role for one specific GABAA receptor subtype which is highly concentrated in young adult MGB. These extrasynaptic 14d subunit containing GABAA receptors show a profound reduction in aged animals. Specific studies will: 1) Determine age-related changes in the subunit makeup and pharmacology of GABAA receptor constructs in the MGB. 2) Determine the role of GABAA receptors in shaping responses to novel and temporally modulated stimuli in young and aged rat MGB neurons using iontophoretic techniques. 3) Determine age-related changes in response to temporally complex and novel stimuli in MGB neurons in unanesthetized rats. Collectively, these studies will begin to characterize the impact of aging on the function of inhibitory GABA circuits in the MGB and may provide a basis for development of selective agents which could potentially ameliorate certain kinds of age-related hearing loss. PUBLIC HEALTH RELEVANCE: Age-related hearing loss is arguably the second or third major malady of industrialized people, affecting 30% of the US population aged 65 to 74 and 50% of the population over 75 years of age and older. Older individuals have more difficulty understanding speech, especially in noise than younger adults. These threshold changes are at least in part, independent of inner ear hair cell loss. Previous studies supported by this grant strongly suggest that, the loss of certain inhibitory neurochemicals in the brain may be responsible for the observed age-related impairments in speech understanding. Preliminary studies suggest that one important auditory brain area, medial geniculate body, displays a profound age-related loss of one kind of inhibitory receptor. Proposed neurochemical studies will attempt to characterize the pharmacologic properties of this inhibitory receptor in young and aged animals. Electrophysiology will attempt to determine the impact of aging on the ability of brain cells in this area to process acoustic information in an unanesthetized rat model of aging. It is hoped that these studies could eventually result in the development of selective new drugs to improve speech understanding in a subset of elderly individuals.

描述（由申请人提供）：年龄相关性听力损失是一种复杂的疾病，影响着30%的65至74岁的美国人口，以及50%的75岁及以上的人口。对具有相似阈值的年轻人和老年人进行的心理声学研究表明，噪音的时间处理和言语理解与年龄有关。这表明老年人在公共场合难以集中注意力和理解讲话，从而有退出社会的倾向。所提出的研究是基于一个潜在的假设，即与年龄相关的听力损失在一定程度上是对听觉外围缓慢进行性脱音的适应性不良的可塑性反应。在许多物种中，声音暴露、化学或物理外周创伤会在听觉通路的多个水平上改变生理反应和成人抑制性神经传递的标记。皮层下颞叶编码研究表明，抑制回路：允许神经反应准确地跟随复杂声信号的包络/颞叶精细结构；参与增益控制；可能会为新颖性检测提供自适应基底（Yu et al., 2009）。在之前的资助期间完成的研究表明，抑制性神经递质在保持编码复杂声学信号的时间和频谱保真度方面发挥着关键作用，因为这些信号是通过听觉途径传播的。这些研究发现，在耳蜗背核和初级听觉皮层中，GABA和甘氨酸能抑制药理学和生理学发生了显著的与年龄相关的变化。提案研究将在衰老背景下检查内侧膝状体（MGB）水平上GABAA受体（GABAARs）的性质。丘脑听觉核接收来自外脑和外脑的上升输入，以及来自听觉和非听觉皮层的网状、边缘和下降输入。拟议的研究试图描述MGB中GABAAR的独特组成及其在注意/新颖性检测和时间加工中的功能参与。拟议的研究将检查MGB中抑制性神经递质GABA作用的年龄相关变化。初步的离子迁移、受体结合和GABAA亚基蛋白的测量表明，一种特异性GABAA受体亚型在年轻人MGB中高度集中。这些含有GABAA受体的突触外14d亚基在老年动物中表现出明显的减少。具体研究将：1)确定MGB中GABAA受体亚基组成和药理学的年龄相关变化。2)利用离子电泳技术确定GABAA受体在形成年轻和老年大鼠MGB神经元对新刺激和时间调节刺激的反应中的作用。3)确定未麻醉大鼠MGB神经元对时间复杂和新颖刺激反应的年龄相关变化。总的来说，这些研究将开始描述衰老对MGB中抑制性GABA回路功能的影响，并可能为开发可能改善某些年龄相关性听力损失的选择性药物提供基础。