Coding in Auditory Neurons: Effects of Amino Acids

描述（由申请人提供）：听力损失是一种复杂的疾病，影响30%的65至74岁的美国人口和50%的75岁及以上人口。心理声学研究在年轻人和老年人具有相似的阈值显示与年龄相关的时间处理和噪声中的语音理解的递减。这表明老年人在公共场合难以注意和理解讲话，导致他们倾向于退出社会。拟议的研究是基于基本假设，这表明，年龄相关的听力损失是，在一定程度上，适应不良的塑性反应，以缓慢进行性deafferentation在听觉周边。在许多物种中，声音暴露、化学或物理性外周创伤改变了听觉通路多个水平的生理反应和成年抑制性神经传递的标志物。皮层下时间编码研究表明，抑制性回路：允许神经反应准确地遵循复杂声学信号的包络/时间精细结构;参与增益控制;可能为新奇检测提供自适应基底（Yu等人，2009年）。在上一个资助期完成的研究表明，抑制性神经递质是至关重要的参与，在保持时间和频谱保真度的编码复杂的声学信号，因为这些信号上升的听觉通路。这些研究发现，在耳蜗背核和初级听觉皮层的GABA和甘氨酸能抑制药理学和生理学的显着年龄相关的变化。提案研究将检查GABAA受体（GABAAR）在老化背景下的内侧膝状体（MGB）水平的性质。听觉丘脑核接受丘系和丘系外的上行输入，以及来自听觉和非听觉皮层的网状、边缘和下行输入。拟议的研究旨在描述MGB中GABAAR的独特组成及其在注意力/新奇检测和时间处理中的功能参与。拟议的研究将检查年龄相关的变化中的作用的抑制性神经递质GABA的MGB。初步离子电渗，受体结合和GABAA亚单位蛋白的措施表明一个特定的GABAA受体亚型，这是高度集中在年轻的成年人MGB的重要作用。这些突触外14 d亚基含有GABAA受体显示出在老年动物中的显著减少。具体研究将：1）确定MGB中GABAA受体结构的亚基组成和药理学的年龄相关变化。2)确定GABAA受体在年轻和老年大鼠MGB神经元使用离子电渗技术塑造新的和时间调制的刺激反应的作用。3)确定未麻醉大鼠MGB神经元对时间复杂和新刺激的年龄相关变化。总的来说，这些研究将开始表征衰老对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。

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.