Neuromodulatory mechanisms of listening effort

听力努力的神经调节机制

• 批准号: 9283542
• 负责人: Matthew J McGinley
• 金额: $ 15.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283542
• 关键词: Acetylcholine; Acoustics; Acute; Address; Animals; Auditory; Auditory area; Axon; Behavior; Behavioral; Biological Models; Calcium; Caliber; Cells; Cholinergic Receptors; Cochlear Implants; Cognitive; Complex; Coupled; Detection; Dissection; Environment; Exhibits; Family; Fatigue; Foundations; Future; Goals; Hearing; Hearing Aids; Human; Image; Impaired cognition; Knowledge; Loudness; Measures; Membrane Potentials; Methodology; Monitor; Mus; Muscarinic Acetylcholine Receptor; Mydriasis; Neuromodulator; Neurons; Nicotine; Noise; Norepinephrine; Patients; Pattern; Phase; Physiological Processes; Plasticizers; Predisposition; Psychometrics; Pupil; Recovery; Recruitment Activity; Research; Resources; Rewards; Scientist; Signal Transduction; Speech; Stress; Temporary Threshold Shift; Testing; Time; Training; Trauma; Walking; Work; auditory processing; behavioral response; cholinergic; experimental study; extracellular; hearing impairment; indexing; interest; mouse model; neuroregulation; noradrenergic; optogenetics; receptor; response; sound; speech processing; sugar; two-photon

Project Summary The primary complaint of patients with hearing loss is the strain required to understand speech in noisy environments. This excessive `listening effort' results in stress, fatigue, and cognitive impairment. A major challenge in mitigating these effects is to identify good measures of the problem. The task-evoked pupil response is an objective and non-invasive measure of listening effort that is well established in hearing research, and increasingly used in studies of hearing loss, hearing aids, and cochlear implants. However, we have little knowledge of the physiological processes tracked by the pupil or the mechanisms of related effects on sound processing. This proposal will determine which neuromodulator(s) are released in association with task-related pupillary measures (Aim 1) and examine the impact of this pupil-indexed modulation on sound processing in auditory cortex (ACtx) of mice (Aim 2). A third aim will assess how hearing loss alters task-related pupil activity for future mechanistic study. Experiments in Aim1 will address the question: What do task-evoked pupillary responses tell us about neuromodulator release in auditory processing? The hypothesis is that ACh and NE release in ACtx are tracked by distinct components of pupillary dynamics during behavior. To test this, I will correlate pupillary measures associated with behavioral responses in a psychometric tone-in-noise detection task, to activity in cortical axons using two-photon calcium imaging. Experiments in Aim 2 will determine mechanisms of the influence of pupil-indexed neuromodulator release on auditory cortical processing. I hypothesize that NE and ACh differentially modulate aspects of spontaneous and sound-driven auditory cortical activity. To test this, I will monitor the pupil while recording membrane potentials or extracellular unit activity in ACtx. I will then optogenetically silence NE/ACh axons or locally block families of NE/ACh receptors in ACtx to dissect the influence of these modulators and their receptors on sound processing. Finally, experiments in Aim 3 will examine changes in the pupillary dynamics in mice resulting from hearing loss induced by acute noise trauma. The hypothesis is that mice with hearing loss exhibit changes in their pupil responses that are similar to those seen in humans. These altered pupillary responses after hearing loss will provide a model system for future mechanistic study of increased listening effort with hearing loss associated with pupillometric readouts. Overall, this proposal will reveal cholinergic and noradrenergic modulatory mechanisms in auditory cortex related to pupil-indexed listening effort. The results will be of interest to scientists and clinicians who: use pupillometry; study neuromodulation; are concerned with listening effort; study the processing of sounds in noisy environments; or study or treat hearing loss. In addition, this proposal will lay a technological and methodological foundation for future mechanistic study of diverse behavioral modulations of auditory processing in mouse models of normal and impaired hearing, including mechanistic dissection of increased listening effort associated with hearing loss.

项目摘要 听力损失患者的主要主诉是在嘈杂的环境中理解语言的困难。 环境。这种过度的“倾听努力”会导致压力、疲劳和认知障碍。一位少校 缓解这些影响的挑战是确定问题的良好措施。任务诱发的瞳孔反应 是一种客观和非侵入性的听力努力测量方法，在听力研究中已经确立，并且 越来越多地用于听力损失、助听器和人工耳蜗术的研究。然而，我们几乎没有 了解学生跟踪的生理过程或对声音的相关影响机制 正在处理。这项建议将决定与任务相关的神经调节剂(S)的释放 瞳孔测量(目标1)，并研究这种瞳孔指数调制对声音处理的影响 小鼠的听觉皮质(ACTx)(目标2)。第三个目标将评估听力损失如何改变与任务相关的小学生活动 为今后的力学研究做准备。Aim1的实验将解决这个问题：任务诱发的瞳孔 反应告诉我们听觉过程中神经调节剂的释放？假设ACh和NE ACTx中的释放是由行为过程中不同的瞳孔动力学成分来跟踪的。为了测试这一点，我将 将与心理测量噪声中音检测任务中的行为反应相关联的瞳孔测量关联起来， 使用双光子钙成像技术检测皮质轴突的活动。目标2中的实验将确定机制 瞳孔指标性神经调节剂释放对听觉皮质处理的影响。我假设东北 ACh对自发和声音驱动的听觉皮质活动的各个方面进行不同的调制。为了测试这一点，我 将在记录ACTx中的膜电位或细胞外单位活动的同时监测瞳孔。那我会的 光遗传沉默ACTx中的NE/ACh轴突或局部阻断NE/ACh受体家族以解剖 这些调节器及其受体对声音处理的影响。最后，目标3中的实验将 检测急性噪声创伤所致听力损失小鼠的瞳孔动力学变化。 这个假设是，听力受损的小鼠的瞳孔反应表现出类似于 在人类身上见过。这些听力损失后改变的瞳孔反应将为未来提供一个模型系统 与斜视读数相关的听力损失增加的听力努力的机制研究。总的来说， 这一建议将揭示听觉皮质中胆碱能和去甲肾上腺素能的调节机制。 以学生为指标的听力努力。这一结果将引起科学家和临床医生的兴趣，他们：使用斜视测量法； 研究神经调节；关注听力努力；研究嘈杂环境中声音的处理 环境；或研究或治疗听力损失。此外，这项建议将奠定一个技术和 未来听觉加工不同行为调节机制研究的方法学基础 在听力正常和受损的小鼠模型中，包括对听力努力增加的机械解剖 与听力损失有关。