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）：与年龄相关的听力损失是一种复杂的疾病，影响了65至74岁的美国人口中的30％，而75岁以上的人口中有50％。阈值相似的年轻和老年受试者的心理声学研究表明，噪声中时间处理和语音理解的年龄相关。这表明，老年人在公共环境中很难理解并理解演讲，从而导致倾向于退出社会。拟议的研究基于基本假设，该假设表明，与年龄相关的听力损失部分是对听觉外围的缓慢进行性逐步脱落的不良塑性反应。在许多物种中，声音暴露，化学或物理外周创伤改变了在听觉途径多个级别的成人抑制性神经传递的生理反应和标志物。皮层下时间编码研究表明，抑制回路：允许神经反应准确地遵循复杂声信号的包膜/时间精细结构；参与收益控制；很可能为新颖性检测提供自适应底物（Yu等，2009）。在上一个赠款期间完成的研究表明，抑制性神经递质与保留编码复杂的声学信号的时间和光谱保真度有关，因为这些信号上升了听觉途径。这些研究发现，在背部耳蜗核和原发性听觉皮层中，GABA和糖抑制性药理学和生理学的年龄有关变化。建议研究将在衰老的背景下检查内侧基因体（MGB）水平上GABAA受体（GABAAR）的性质。听觉丘脑核从听觉和非审计皮层中收到了尼斯和省级的上升输入以及网状，边缘和下降的输入。拟议的研究旨在表征MGB中GABAAR的独特构成及其在注意力/新颖性检测和时间处理中的功能参与。拟议的研究将检查与年龄相关的抑制性神经递质GABA在MGB中的作用变化。初步的离子疗法，受体结合和GABAA亚基蛋白的测量表明，一种特定的GABAA受体亚型的重要作用，该蛋白在年轻的成人MGB中高度集中。这些含有GABAA受体的外鼻外14D亚基在老年动物中显示出明显的减少。具体研究将：1）确定MGB中GABAA受体构建体的亚基化妆和药理学的变化。 2）确定GABAA受体在使用离子噬菌技术中对年轻和老年大鼠MGB神经元中对新颖和暂时调节刺激的反应的作用。 3）确定对临时复杂和新颖的刺激的变化，其中MGB神经元中的一体化大鼠中的MGB神经元中的变化。总的来说，这些研究将开始表征衰老对MGB中抑制性GABA电路功能的影响，并可能为选择性剂的发展提供基础，从而有可能改善某些与年龄相关的听力损失。 公共卫生相关性：与年龄相关的听力损失可以说是工业化人群的第二或第三个主要疾病，影响了75岁以上的65至74％和50％的美国人口中的30％。老年人在理解语音方面有更多的困难，尤其是在噪音中，比年轻人更困难。这些阈值的变化至少部分与内耳毛细胞损失无关。这项赠款支持的先前研究强烈表明，大脑中某些抑制性神经化学物质的丧失可能是导致观察到的与年龄相关的言语理解障碍的原因。初步研究表明，一个重要的听觉大脑区域，内侧遗传体，表现出与年龄相关的一种抑制性受体的严重丧失。拟议的神经化学研究将尝试表征这种抑制性受体在年轻动物和老年动物中的药理特性。电生理学将试图确定衰老对该区域中脑细胞在未经麻醉大鼠衰老模型中处理声学信息的能力的影响。希望这些研究最终可以导致选择性新药的发展，以提高老年人一部分的语音理解。