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.

与年龄相关的中枢听觉功能下降会显着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，《柳叶刀》委员会 2017 年的一份报告将听力损失视为发展的最大可改变风险因素。认知能力下降、过度吸烟、高血压、缺乏运动和社交孤立 值得注意的是，2019 年的一项大规模研究发现，即使是轻度听力损失（即仍在正常范围内），也与认知能力下降产生更密切的关联。目前，对于与年龄相关的中枢听力下降还没有有效的治疗方法——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力功能，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，该提案的目标是开发衰老小鼠和人类听觉处理改变的生物标志物，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听力正常化的假设。中央审计员由于尼古丁可以增强皮质和认知功能，制药公司正在开发类似尼古丁的药物来治疗衰老过程中的认知缺陷。这些药物不会上瘾（与烟草中的尼古丁不同），但尼古丁在局部或口服时也不会上瘾。然而，除了作为戒烟的辅助手段外，它的临床益处尚未被开发利用：1）急性尼古丁通过刺激剩余的抑制性神经元来补偿与年龄相关的抑制作用的下降； 2) 慢性尼古丁暴露 (CNE) 上调烟碱乙酰胆碱受体 (nAChR)；因此，3) 急性尼古丁和/或 CNE 将减少或逆转与年龄相关的听力下降。人类在细胞（小鼠体外脑切片）、神经系统（小鼠体内生理学；人脑成像和脑电图）和行为（人类心理声学）水平上的研究。目标 1 将在小鼠中确定急性尼古丁或 CNE 是否可以逆转与年龄相关的听觉频谱时间处理下降，并表征相关的细胞机制；目标 2 将利用在人类中识别听觉皮层感受野特性中与年龄相关的变化。新颖的功能磁共振成像技术，并使用心理声学、功能磁共振成像和脑电图确定尼古丁是否逆转这些变化。该项目采用多方面、平行的方法，对小鼠和人类进行测试：1）检查听觉。多个成年年龄的处理；2）在两个物种中使用相似的声音刺激，考虑到听力的物种差异，以针对共同的机制；3）测试尼古丁的影响，将促进从细胞机制的跨层面的综合理解。感知，并促进基于尼古丁的治疗方法向临床人群的转化。