Neuromodulatory mechanisms of listening effort

听力努力的神经调节机制

• 批准号: 9172281
• 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/9172281
• 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; Monitor; Mus; Muscarinic Acetylcholine Receptor; Mydriasis; Neuromodulator; Neurons; Noise; Norepinephrine; Patients; Pattern; Physiological Processes; Predisposition; Process; Psychometrics; Pupil; Recovery; Research; Resources; Rewards; Scientist; Signal Transduction; Speech; Stress; Temporary Threshold Shift; Testing; Time; Training; Trauma; Walking; Work; behavioral response; cholinergic; extracellular; hearing impairment; indexing; interest; mouse model; neuroregulation; noradrenergic; receptor; research study; 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.

项目概要 听力损失患者的主要抱怨是在嘈杂的环境中理解言语所需的压力 环境。这种过度的“倾听努力”会导致压力、疲劳和认知障碍。一个专业 减轻这些影响的挑战是确定解决问题的良好措施。任务诱发的瞳孔反应 是听力研究中公认的一种客观且非侵入性的听力努力测量方法，并且 越来越多地用于听力损失、助听器和人工耳蜗的研究。然而我们却拥有很少 了解瞳孔跟踪的生理过程或对声音的相关影响机制 加工。该提案将确定与任务相关的神经调节剂的释放 瞳孔测量（目标 1）并检查这种瞳孔索引调制对声音处理的影响 小鼠听觉皮层 (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学生活动 以供将来的机理研究。 Aim1 中的实验将解决以下问题：任务诱发的瞳孔有何作用？ 反应告诉我们听觉处理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瞳孔动力学的不同组成部分跟踪的。为了测试这一点，我将 将瞳孔测量与心理测量噪声检测任务中的行为反应相关联， 使用双光子钙成像来观察皮质轴突的活动。目标 2 中的实验将确定机制 瞳孔索引神经调节剂释放对听觉皮层处理的影响。我假设 NE 和乙酰胆碱对自发和声音驱动的听觉皮层活动进行差异性调节。为了测试这一点，我 将监测瞳孔，同时记录 ACtx 中的膜电位或细胞外单位活动。然后我会 光遗传学沉默 NE/ACh 轴突或局部阻断 ACtx 中的 NE/ACh 受体家族，以剖析 这些调制器及其受体对声音处理的影响。最后，目标 3 中的实验将 检查因急性噪音创伤引起的听力损失而引起的小鼠瞳孔动力学的变化。 假设患有听力损失的小鼠的瞳孔反应发生了与那些小鼠相似的变化。 见于人类。听力损失后这些瞳孔反应的改变将为未来提供一个模型系统 与瞳孔测量读数相关的听力损失增加的听力努力的机制研究。全面的， 该提案将揭示与听觉皮层相关的胆碱能和去甲肾上腺素能调节机制 学生索引的听力努力。研究结果将引起以下科学家和临床医生的兴趣：使用瞳孔测量法； 研究神经调节；关心倾听的努力；研究噪声中声音的处理 环境；或研究或治疗听力损失。此外，该提案还将奠定技术和 听觉处理多种行为调节的未来机制研究的方法论基础 在正常和听力受损的小鼠模型中，包括增加听力努力的机械解剖 与听力损失有关。