Age-related GABAergic loss in the central auditory circuits

中枢听觉回路中与年龄相关的 GABA 能丧失

• 批准号: 10221666
• 负责人: Jeffrey Garrett Mellott
• 金额: $ 33.15万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221666
• 关键词: Acoustics; Address; Affect; Age; Aging; Antibodies; Appearance; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Auditory Threshold; Auditory area; Auditory system; Behavior; Cells; Cochlea; Data; Degenerative Disorder; Detection; Disease; Down-Regulation; Electron Microscopy; Environment; Financial compensation; Frequencies; Future; Glutamates; Goals; Gold; Hearing problem; Immunochemistry; Immunoelectron Microscopy; Impairment; Inferior Colliculus; Knowledge; Label; Lead; Life; Measures; Midbrain structure; Neurons; Neurotransmitters; Noise; Pathway interactions; Perception; Peripheral; Phenotype; Physiology; Play; Presbycusis; Process; Publishing; Reflex action; Reporting; Research; Resolution; Risk Factors; Role; Signal Transduction; Speech; Synapses; System; Techniques; Testing; Therapeutic; Time; TimeLine; Viral; age related; aging auditory system; auditory nuclei; auditory processing; base; design; emerging adult; experimental study; gamma-Aminobutyric Acid; hearing impairment; light microscopy; neural circuit; prepulse inhibition; receptor; response; sound; therapeutically effective

Project Summary Our long-term goal is to understand the relationship between peripheral and central changes in the auditory system during age-related hearing loss (ARHL). GABA, an inhibitory neurotransmitter critical for precise temporal processing, is downregulated in the central auditory system during aging. This loss of GABA has been best documented in the inferior colliculus (IC), an auditory nucleus that gives rise to ascending circuits that carry temporally precise signals to the auditory cortex for perception and descending circuits that play a pivotal role in the temporal processing of interpreting speech from noise. Recent studies hypothesize that the downregulation of GABA is a homeostatic response to “re-up” the gain in central neurons as the cochlear input is diminished. However, our understanding of GABAergic function in the aging IC is inadequate due to the lack of information about the relationship of GABA loss to increasing hearing deficits, about which specific IC circuits lose GABA, and how those circuits respond during aging. Our central hypothesis is that age-related GABAergic downregulation in the IC occurs prior to the onset of auditory processing deficits and in two stages: an initial loss of GABA prior to age-related auditory processing deficits that is associated with descending IC circuits, and a subsequent loss associated with the ascending IC circuits. The objective of this proposal is to determine where in the IC age-related changes of GABA occur and if so, do these changes occur before the onset of auditory processing deficits. The experiments will combine data from gap detection using the prepulse inhibition of the acoustic startle, envelope following responses, auditory brainstem responses, immunochemistry and immunoelectron microscopy-intersectional viral tracing to determine age-related GABAergic changes in the IC that occur before hearing deficits. Examining the relationship between the loss of GABAergic cells, boutons and synapses in the aging IC before the onset of hearing deficits is the focus of Aim 1. Aim 2 will determine if specific IC circuits lose GABAergic input with age and if so, when those losses occur relative to each other. Aim 3 will identify when inhibitory and excitatory IC circuits change their GABAA receptor subunit composition to compensate for the declining levels of GABAergic input during ARHL. Data generated from these three Aims will move the field forward by establishing precise points in time when age-related changes in specific circuits of the central auditory system occur in relation to hearing loss. The results will provide essential information for designing and interpreting future experiments with viral tracing, physiology and behavior to investigate GABAergic function in the aging auditory system.

项目摘要 我们的长期目标是了解听觉的外围和中心变化之间的关系 与年龄有关的听力损失（ARHL）期间的系统。 GABA，一种至关重要的抑制性神经递质 临时处理，在老化期间的中央听觉系统中被下调。 GABA的损失有 最好记录在下丘（IC）中，这是一种听觉核，产生上升的电路 那将暂时精确的信号带到听觉皮层，以进行感知和降低的圆圈 关键作用在解释噪声解释语音的临时处理中。最近的研究假设 GABA的下调是对中央神经元的“重新提升”作为人工耳蜗输入的“重新提升”增益的一种稳态反应 减少了。但是，由于缺乏，我们对衰老IC中GABA能功能的理解不足 有关GABA损失与增加听力防御的关系的信息，有关哪种特定IC的信息 电路失去了GABA，以及这些电路在衰老期间的响应方式。 我们的中心假设是，与年龄相关的GABA能下调发生在开始之前 听觉处理定义了两个阶段：在与年龄相关的听觉处理之前，GABA的初始损失 与下降IC电路相关的缺陷，以及随后与上升IC相关的损失 电路。该提案的目的是确定GABA与IC年龄相关的变化发生的位置 如果是这样，这些更改是否发生在听觉处理缺陷开始之前。实验将结合 来自GAP检测的数据，使用对声学惊吓的预硫抑制，包膜以下响应， 听觉的脑干反应，免疫化学和免疫电子显微镜间接病毒跟踪 确定与年龄相关的GABA能变化，在听到缺陷之前发生的IC。检查 在衰老IC中，GABA能细胞，胸子和突触的丧失之间的关系 听力定义是目标1的重点。AIM2将确定特定的IC电路是否随着年龄的增长而失去GABA能输入 如果是这样，当这些损失相对于彼此发生时。 AIM 3将确定何时抑制性和兴奋性IC 电路更改其GABAA受体亚基组成，以补偿GABA能量的下降 ARHL期间的输入。 从这三个目标产生的数据将通过在时间上建立精度点来向前推进现场 与听力损失有关的中央听觉系统特定电路的年龄相关变化。这 结果将为设计和解释以病毒追踪设计和解释未来的实验提供必不可少的信息， 研究老化听觉系统中GABA能功能的生理和行为。