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衰退会显著影响老年人的生活质量，言语感知受损会导致抑郁、社会孤立和认知能力下降的风险增加。《柳叶刀》委员会2017年的一份报告指出，听力损失是导致认知能力下降的最大可改变风险因素，超过了吸烟、高血压、缺乏锻炼和社会孤立。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，对于与年龄相关的中枢性听力下降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。本提案的目标是开发衰老小鼠和人类听觉加工改变的生物标志物，并使用这些生物标志物来验证尼古丁可以使这些与年龄相关的中央性听觉缺陷正常化的假设。由于尼古丁能增强大脑皮层和认知功能，制药公司正在开发类似尼古丁的药物，以治疗衰老过程中的认知缺陷。这些药物不成瘾性（不像烟草中的尼古丁），但尼古丁在局部或口服时也不会成瘾性。然而，除了作为戒烟的辅助手段外，它的临床效益尚未得到充分利用。我们假设：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能力下降；2)慢性尼古丁暴露（CNE）上调烟碱乙酰胆碱受体（nAChRs）；因此，3)急性尼古丁和/或CNE将减少或逆转与年龄相关的听觉衰退。我们将在细胞（小鼠体外脑切片）、神经系统（小鼠体内生理学；人脑成像和脑电图）和行为（人类心理声学）水平上对小鼠和人类的这些假设进行测试。目的1将在小鼠中确定急性尼古丁或CNE是否逆转与年龄相关的听觉光谱处理下降，并描述相关的细胞机制。Aim 2将利用新型功能磁共振成像技术识别人类听觉皮层感受野特性的年龄相关变化，并利用心理声学、功能磁共振成像和脑电图确定尼古丁是否逆转这些变化。这个项目的特点是在小鼠和人类中采用多方面的并行方法。每个目标将：1)检查多个成人年龄的听觉加工；2)在两个物种中使用相似的声刺激，考虑到物种在听力上的差异，以共同机制为目标；3)测试尼古丁的效果。一个成功的结果将促进从细胞机制到感知的各个层面的综合理解，并促进将基于尼古丁的治疗方法转化为临床人群。