Neuromodulatory mechanisms of listening effort

项目摘要 听力损失患者的主要抱怨是在嘈杂的环境中理解语音所需的压力。 环境.这种过度的“倾听努力”会导致压力、疲劳和认知障碍。一个主要 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 是一种客观和非侵入性的听力努力的测量方法，在听力研究中得到了很好的建立， 越来越多地用于听力损失、助听器和人工耳蜗的研究。然而，我们几乎没有 对瞳孔跟踪的生理过程或对声音的相关影响机制的了解 处理.该提案将确定哪些神经调质与任务相关的释放有关。 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）（目的2）。第三个目标是评估听力损失如何改变与任务相关的瞳孔活动 未来的机械研究。目标1中的实验将解决这个问题：任务诱发的瞳孔 反应告诉我们听觉处理中神经调质的释放？假设ACh和NE ACtx的释放通过行为期间瞳孔动力学的不同组分来跟踪。为了验证这一点，我将 将与心理测量噪声中音调检测任务中的行为响应相关联的瞳孔测量相关联， 大脑皮层轴突的活动。目标2中的实验将确定机制 瞳孔指数神经调质释放对听觉皮层处理的影响。我假设， 和ACh差异调节自发和声音驱动的听觉皮层活动的方面。为了验证这个，我 将监测瞳孔，同时记录ACtx中的膜电位或细胞外单位活性。然后我将 光遗传学沉默NE/ACh轴突或局部阻断ACtx中的NE/ACh受体家族，以分析 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 研究急性噪声损伤引起的小鼠听力损失引起的瞳孔动力学变化。 假设是，听力损失的小鼠的瞳孔反应表现出与听力损失小鼠相似的变化 在人类身上看到的。这些听力损失后改变的瞳孔反应将为未来的研究提供一个模型系统。 与瞳孔测量读数相关的听力损失增加听力努力的机制研究。总的来说， 这一提议将揭示听觉皮层胆碱能和去甲肾上腺素能调节机制， 学生的听力努力。这些结果将对科学家和临床医生感兴趣，他们：使用瞳孔测量; 研究神经调节;关注听力;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，该提案还将奠定技术和 为将来研究听觉加工的多种行为调制机制奠定了方法学基础 在正常和听力受损的小鼠模型中，包括对增加的听力努力的机械解剖 与听力损失有关。

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.