Using nicotine to reverse age-related auditory processing deficits

与年龄相关的中枢听觉功能下降显著影响老年人的生活质量，言语感知受损会导致抑郁、社交孤立和认知能力下降的风险增加。2017年柳叶刀委员会的一份报告指出，听力损失是导致认知能力下降、过度吸烟、高血压、缺乏锻炼和社交孤立的最大可修改风险因素。值得注意的是，2019年的一项大规模研究发现，即使是轻微的听力损失，即仍在正常范围内，也会与认知能力下降产生更密切的联系。目前，还没有有效的治疗老年性中枢性听力下降的方法--助听器只能解决听力问题--也没有药物治疗。理想情况下，药物治疗与助听器和行为训练相结合可以恢复听觉功能，但药物治疗的发展需要更好地了解候选药物改善听力的机制。这项提议的目标是开发衰老小鼠和人类听觉处理改变的生物标记物，并使用这些生物标记物来检验尼古丁可以使这些与年龄相关的中枢听觉缺陷正常化的假设。由于尼古丁增强了皮质和认知功能，制药公司正在开发尼古丁类药物，以针对衰老过程中的认知缺陷。这些药物不会上瘾(不像烟草中的尼古丁)，但局部或口服尼古丁也不会上瘾。然而，除了作为戒烟的辅助手段外，它的临床益处还没有被开发出来。我们假设：1)急性尼古丁通过兴奋剩余的抑制性神经元来补偿与年龄相关的抑制下降；2)慢性尼古丁暴露(CNE)上调烟碱型乙酰胆碱受体(NAChRs)；3)急性尼古丁和/或CNE将减少或逆转与年龄相关的听觉下降。我们将在细胞(小鼠体外脑切片)、神经系统(小鼠体内生理学；人脑成像和脑电)和行为(人类心理声学)的水平上在小鼠和人类身上测试这些假说。目的1将在小鼠身上确定急性尼古丁或CNE是否逆转了与年龄相关的听觉频谱处理能力的下降，并描述了相关的细胞机制。目标2将使用新的fMRI技术在人类中识别与年龄相关的听觉皮质感受场特性的变化，并使用心理声学、fMRI和EEG确定尼古丁是否逆转这些变化。这个项目的特点是在老鼠和人类身上采用了一种多方面的平行方法。每个目标将：1)检查多个成年年龄的听觉处理；2)在两个物种中使用相似的声音刺激，考虑到物种听力的差异，以确定共同的机制；3)测试尼古丁的影响。一个成功的结果将促进从细胞机制到感知的跨层次的综合理解，并促进以尼古丁为基础的治疗方法向临床人群的转化。

Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. A 2017 Lancet Commission report cites hearing loss as the largest modifiable risk factor for developing cognitive decline, exceeding smoking, high blood pressure, lack of exercise and social isolation. Remarkably, a 2019 large-scale study found that even mild hearing loss, i.e., still within the normal range, produced an even closer association with cognitive decline. Currently, there is no effective therapy for age-related central auditory decline—hearing aids only address audibility—and no drug treatment. Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing. The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits. Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking. We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline. We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics). Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms. Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG. This project features a multifaceted, parallel approach in mouse and human. Each Aim will: 1) examine auditory processing at multiple adult ages; 2) use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms; 3) test the effects of nicotine. A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.