Using nicotine to reverse age-related auditory processing deficits

使用尼古丁逆转与年龄相关的听觉处理缺陷

• 批准号: 10543546
• 负责人: Raju Metherate
• 金额: $ 58.16万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543546
• 关键词: Accounting; Acoustics; Acute; Address; Adult; Affect; Age; Aging; Area; Attention; Auditory; Auditory Perception; Auditory area; Behavior; Behavioral; Biological Markers; Brain; Brain imaging; Cells; Chronic; Clinical; Cognitive; Cognitive deficits; Compensation; Detection; Development; Disease; Drug Combinations; Drug Kinetics; Drug Targeting; Elderly; Electroencephalography; Electrophysiology (science); Environment; Exercise; FVB Mouse; Frequencies; Functional Magnetic Resonance Imaging; Goals; Hearing; Hearing Aids; Human; Hypertension; Image; Impaired cognition; Impairment; In Vitro; Interneurons; Measures; Mental Depression; Mus; Nicotine; Nicotinic Receptors; Noise; Normal Range; Oral; Outcome; Outcome Measure; Perception; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacotherapy; Physiological; Physiology; Population; Presbycusis; Property; Psychoacoustics; Quality of life; Reporting; Rest; Risk; Risk Factors; Route; Sensory; Slice; Smoking; Social isolation; Speech; Speech Perception; Stimulus; System; Techniques; Testing; Therapeutic; Tobacco; Topical application; Training; Translations; absorption; age effect; age related; auditory processing; biomarker identification; cognitive enhancement; cognitive function; density; distraction; drug candidate; drug development; effective therapy; functional magnetic resonance imaging/electroencephalography; hearing impairment; improved; in vivo; inhibitory neuron; modifiable risk; neural; nicotine exposure; nicotine use; non-smoker; novel; preclinical development; receptive field; reduce symptoms; smoking cessation; sound; species difference

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.

与年龄相关的中央听觉功能下降显着影响最古老的生活质量，言语感知受损，导致抑郁症，社会隔离和认知能力下降的风险增加。 2017年柳叶刀委员会报告的听力损失是发展认知能力下降，超越吸烟，高血压，缺乏运动和社会隔离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，即使是在正常范围内的听力损失，也会与认知能力下降更紧密。当前，与年龄相关的中央听觉下降（Hearing Hearing Airs）尚无有效的治疗方法，仅解决可审核性，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的结合可以恢复听觉功能，但是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。该提案的目标是开发衰老的小鼠和人类中听觉加工改变的生物标志物，并使用这些生物标志物来检验尼古丁可以使这些与年龄相关的中央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，因此制药公司正在开发类似尼古丁的药物，以靶向衰老的认知缺陷。这些药物是非添加的（与烟草中的尼古丁不同），但是当局部或口服给予尼古丁时，尼古丁也不添加。但是，除了作为停止吸烟的帮助外，尚未探索其临床益处。我们假设：1）急性尼古丁通过激发剩余的抑制性神经元来弥补与年龄相关的抑制作用下降； 2）慢性尼古丁暴露（CNE）上调尼古丁乙酰胆碱受体（NACHRS）；因此，3）急性尼古丁和/或CNE将减少或扭转与年龄相关的听觉下降。我们将在小鼠和人类中在细胞（小鼠体外脑切片），神经元系统（小鼠体内生理学；人脑成像和脑电图）和行为（人类心理声学）的水平上测试这些假设。 AIM 1将在小鼠中确定与年龄相关的听觉谱量表处理是否通过急性尼古丁或CNE逆转，并表征相关的细胞机制。 AIM 2将在人类中，使用新颖的fMRI技术在人类中，在听觉皮层中与年龄相关的变化，并确定尼古丁是否使用心理声学，fMRI和EEG逆转了这些变化。该项目采用了鼠标和人类的多方面，平行的方法。每个目标都将：1）检查多个成人年龄的听觉处理； 2）在这两个物种中使用类似的声学刺激，考虑了听力的物种差异，以靶向共同的机制； 3）测试尼古丁的作用。成功的结果将促进从细胞机制到感知的跨越水平的综合理解，并促进将基于尼古丁的治疗治疗转化为临床人群。