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.

项目摘要 我们的长期目标是了解听觉中枢和外周变化之间的关系， 年龄相关性听力损失（ARHL）GABA是一种抑制性神经递质， 在衰老过程中，中枢听觉系统中的时间处理下调。这种GABA的缺失 在下丘（IC）中有最好的记录，下丘是一个产生上行回路的听觉核团 它将时间上精确的信号传送到听觉皮层，用于感知和下行回路， 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的下调是对作为耳蜗输入的中枢神经元中的增益“重新增加”的稳态响应 已经减少了。然而，由于缺乏对GABA能在衰老IC中的作用的研究， 关于GABA损失与听力缺陷增加的关系的信息，关于哪种特定的IC 电路失去GABA，以及这些电路在衰老过程中如何反应。 我们的中心假设是，年龄相关的GABA能下调IC发生在发病前， 听觉处理缺陷，并在两个阶段：GABA的初始损失之前，年龄相关的听觉处理 与下行IC电路相关的缺陷，以及与上行IC相关的后续损失 电路.本提案的目的是确定在IC中与年龄相关的GABA变化发生的位置， 如果是，这些变化是否发生在听觉处理缺陷出现之前。这些实验将联合收割机 来自使用声惊吓的前脉冲抑制的间隙检测的数据，包络跟随响应， 听觉脑干反应，免疫化学和免疫电镜-交叉病毒示踪， 确定在听力缺陷之前发生的IC中与年龄相关的GABA能变化。检查 衰老前IC中GABA能细胞、终扣和突触的丢失之间的关系 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，当这些损失相对于彼此发生时。目的3将确定何时抑制性和兴奋性IC 电路改变其GABAA受体亚单位组成，以补偿GABA能水平的下降， 在ARHL期间输入。 从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中与年龄相关的变化与听力损失有关。的 结果将为设计和解释未来的病毒追踪实验提供必要的信息， 生理学和行为学研究GABA能功能在老化的听觉系统。

项目成果

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

• DOI: 10.1016/j.neurobiolaging.2021.04.001
• 发表时间: 2021-09
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Mafi AM;Russ MG;Hofer LN;Pham VQ;Young JW;Mellott JG
• 通讯作者: Mellott JG

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

• DOI: 10.1016/j.neurobiolaging.2022.08.007
• 发表时间: 2022-12
• 期刊: NEUROBIOLOGY OF AGING
• 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.

Age-related upregulation of perineuronal nets on inferior collicular cells that project to the cochlear nucleus.

与人工耳蜗核的下胶细胞上周围神经元网的年龄相关的上调。

• DOI: 10.3389/fnagi.2023.1271008
• 发表时间: 2023
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

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。

• DOI: 10.1002/cne.25515
• 发表时间: 2023
• 期刊: The Journal of comparative neurology
• 作者: Haragopal,Hariprakash;Mellott,JeffreyG;Dhar,Matasha;Kanel,Alinea;Mafi,Amir;Tokar,Nick;Winters,BradleyD
• 通讯作者: Winters,BradleyD

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。

• DOI: 10.1016/j.tma.2023.04.001
• 发表时间: 2023
• 期刊: Translational medicine of aging
• 作者: Koehler,ChristinaC;Almassri,LailaS;Tokar,Nick;Mafi,AmirM;O'Hara,MitchellJ;Young,JesseW;Mellott,JeffreyG
• 通讯作者: Mellott,JeffreyG