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外周和中枢变化之间的关系 年龄相关性听力损失(ARHL)期间的系统。GABA是一种抑制神经递质，对精确度 在衰老过程中，时间处理在中枢听觉系统中被下调。这种GABA的丧失已经 最好的记录是在下丘(IC)，这是一个产生上升回路的听觉核团 将时间上精确的信号传送到听觉皮质进行感知和下行电路 在从噪声中解释语音的时间处理中起着关键作用。最近的研究假设， GABA的下调是一种动态平衡反应，“重新上调”中枢神经元的增益，作为耳蜗的输入 被削弱了。然而，由于缺乏对老化IC中GABA能功能的了解，我们对其认识还不够充分 关于GABA损失与听力障碍增加的关系的信息，关于哪种特定的IC 电路失去GABA，以及这些电路在老化过程中的反应。 我们的中心假设是IC中与年龄相关的GABA能下调发生在 听觉加工缺陷和两个阶段：与年龄相关的听觉加工之前GABA的初始损失 与下行IC电路相关的损耗，以及与上升IC相关的后续损耗 电路。这项建议的目的是确定在IC中与年龄相关的GABA变化发生在哪里，以及 如果是这样的话，这些变化是在听觉处理缺陷出现之前发生的吗？这些实验将结合起来 来自使用声惊吓的预脉冲抑制的间隙检测的数据，包络跟随响应， 听性脑干反应、免疫化学和免疫电子显微镜-横截面病毒示踪 确定在听力障碍之前发生在IC中的与年龄相关的GABA能变化。检查 老年IC发病前GABA能细胞、突触和突触丢失的关系 听力障碍是目标1的重点。目标2将确定特定的IC电路是否会随着年龄的增长而失去GABA能输入 如果是这样的话，这些损失是在什么时候发生的。AIM 3将识别抑制性和兴奋性IC 电路改变其GABAA受体亚单位组成以补偿GABA能 在ARHL期间输入。 从这三个目标生成的数据将通过建立准确的时间点来推动领域向前发展 中枢听觉系统特定回路的年龄相关变化与听力损失有关。这个 结果将为设计和解释未来的病毒跟踪实验提供必要的信息， 研究衰老听觉系统中GABA能功能的生理学和行为学。