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: 10669169
• 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/10669169
• 关键词: Acceleration; Acoustics; Address; Affect; Age; Aging; Antibodies; Appearance; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Auditory Threshold; Auditory area; Auditory system; Behavior; Cells; Cochlea; Compensation; Data; Degenerative Disorder; Detection; Disease; Down-Regulation; Electron Microscopy; Environment; Frequencies; Future; Glutamates; Goals; Gold; Hearing problem; Immunochemistry; Immunoelectron Microscopy; Impairment; Inferior Colliculus; Knowledge; Label; Life; Measures; Midbrain structure; Neurons; Neurotransmitters; Noise; Pathway interactions; Perception; Peripheral; Persons; Phenotype; Physiology; Play; Presbycusis; Process; Publishing; Reflex action; Reporting; Research; Resolution; Risk Factors; Role; Signal Transduction; Speech; Synapses; System; Techniques; Testing; Therapeutic; Time; Viral; age related; aging auditory system; auditory nuclei; auditory processing; design; emerging adult; experimental study; gamma-Aminobutyric Acid; hearing impairment; light microscopy; neural circuit; prepulse inhibition; receptor; response; sound; therapeutically effective; timeline

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.

项目概要 我们的长期目标是了解听觉的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 是一种对精确性至关重要的抑制性神经递质。 衰老过程中，中枢听觉系统的时间处理功能会下调。 在下丘（IC）中得到了最好的记录，下丘是一个产生上行回路的听觉核 将时间上精确的信号传送到听觉皮层进行感知，而下行电路则发挥作用 最近的研究表明，在从噪声中解释语音的时间处理中发挥着关键作用。 GABA 下调是一种稳态反应，可“重新增加”中枢神经元作为耳蜗输入的增益 然而，由于缺乏，我们对老化 IC 中 GABA 功能的了解还不够。 有关 GABA 损失与听力缺陷增加之间关系的信息，具体 IC 电路失去 GABA，以及这些电路在老化过程中如何反应。 我们的中心假设是，IC 中与年龄相关的 GABA 能下调发生在 听觉处理缺陷分为两个阶段：在与年龄相关的听觉处理之前，GABA 最初丧失 与下降 IC 电路相关的缺陷，以及与上升 IC 相关的后续损耗 该提案的目的是确定 IC 中与年龄相关的 GABA 变化发生的位置以及 如果是这样，这些变化是否发生在听觉处理缺陷出现之前？这些实验将结合起来。 使用声惊吓的前脉冲抑制包络进行间隙检测的数据，遵循响应， 听觉脑干反应、免疫化学和免疫电子显微镜-交叉病毒追踪 确定听力缺陷之前发生的 IC 中与年龄相关的 GABA 变化。 老化IC中GABA能细胞、突触和突触的损失之间的关系。 听力缺陷是目标 1 的重点。目标 2 将确定特定 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，目标 3 将确定何时发生抑制性 IC 和兴奋性 IC。 电路改变其 GABAA 受体亚基组成以补偿 GABA 能水平的下降 ARHL 期间输入。 这三个目标生成的数据将通过建立精确的时间点来推动该领域向前发展 中枢听觉系统特定回路的年龄相关变化与听力损失有关。 结果将为设计和解释未来的病毒追踪实验提供重要信息， 生理学和行为研究衰老听觉系统中的 GABA 功能。

项目成果

Age-related ultrastructural changes in the lateral cortex of the inferior colliculus.

下丘外侧皮质与年龄相关的超微结构变化。

• 发表时间: 2022-12
• 影响因子: 4.2
• 作者: Mafi, Amir M;Tokar, Nick;Russ, Matthew G;Barat, Oren;Mellott, Jeffrey G
• 通讯作者: Mellott, Jeffrey G

Inferior collicular cells that project to the auditory thalamus are increasingly surrounded by perineuronal nets with age.

随着年龄的增长，投射到听觉丘脑的下丘细胞越来越多地被神经周围网包围。

• 发表时间: 2021
• 影响因子: 4.2
• 作者: Mafi, Amir M;Russ, Matthew G;Hofer, Lindsay N;Pham, Vincent Q;Young, Jesse W;Mellott, Jeffrey G
• 通讯作者: Mellott, Jeffrey G

Age-related Changes of GAD1 mRNA Expression in the Central Inferior Colliculus.

中央下丘 GAD1 mRNA 表达的年龄相关变化。

• 发表时间: 2023
• 作者: Koehler, Christina C;Almassri, Laila S;Tokar, Nick;Mafi, Amir M;O'Hara, Mitchell J;Young, Jesse W;Mellott, Jeffrey G
• 通讯作者: Mellott, Jeffrey G

Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of Mongolian gerbils.

蒙古沙鼠外侧上橄榄色抑制性和兴奋性细胞类型的音位分布和下丘投影模式。

• 发表时间: 2022-02
• 作者: Mellott, Jeffrey G;Dhar, Matasha;Mafi, Amir;Tokar, Nick;Winters, Bradley D
• 通讯作者: Winters, Bradley D

Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of mice.

小鼠外侧上橄榄抑制性和兴奋性细胞类型的音位分布和下丘投射模式。

• 发表时间: 2023-10
• 作者: Haragopal, Hariprakash;Mellott, Jeffrey G;Dhar, Matasha;Kanel, Alinea;Mafi, Amir;Tokar, Nick;Winters, Bradley D
• 通讯作者: Winters, Bradley D