Extratelencephalic contributions to auditory categorization

端脑外对听觉分类的贡献

• 批准号: 10711643
• 负责人: Ross Stewart Williamson
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711643
• 关键词: Acceleration; Accounting; Address; Adult; Affect; Age Months; Age Years; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Area; Arousal; Atrophic; Attention; Auditory; Auditory area; Auditory system; Behavioral; Biochemical; Chronic; Cognition; Cognitive deficits; Data; Decision Making; Dementia; Diameter; Disease Progression; Face; Functional disorder; Future; Goals; Health; Hippocampus; Human; Hyperactivity; Impaired cognition; Impairment; Individual; Investigation; Knock-in Mouse; Knowledge; Link; Memory; Memory impairment; Monitor; Motor Activity; Movement; Mus; Neocortex; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Noise-Induced Hearing Loss; Pathogenesis; Pathologic; Pathology; Performance; Presbycusis; Process; Pupil; Risk; Risk Factors; Route; Senile Plaques; Sensory; Shapes; Source; Stereotyping; Synapses; Time; Wild Type Mouse; abeta accumulation; age group; age related; auditory categorization; auditory stimulus; cognitive function; cohort; entorhinal cortex; experimental study; functional disability; hearing impairment; hyperphosphorylated tau; in vivo; information processing; insight; member; memory encoding; modifiable risk; mouse model; neocortical; nerve supply; neural; neural circuit; neuroinflammation; neuronal circuitry; neuropathology; noise exposure; novel; optogenetics; pre-clinical; response; tau Proteins; tau aggregation

PROJECT SUMMARY Hearing loss occurs in ~80% of adults over 65 years of age and is considered to be the most heavily contributing modifiable risk factor to dementia. Alzheimer’s disease (AD) is the most common form of age-related dementia. Overwhelming recent evidence suggests an association between hearing loss, AD neuropathology, and memory function. Memory encoding is known to require an intact entorhinal-hippocampal circuit and this circuitry is severely affected in AD. Recent studies, including our own, have begun to tease apart the anatomical route that auditory information takes to reach the hippocampus (HPC) through the entorhinal cortex (EC). However, no study to date has comprehensively investigated how noise-induced hearing loss (NIHL) affects neuronal circuit integrity and integrated these findings into the neuropathological and behavioral changes observed in AD patients. To address this gap in knowledge, we will utilize a recently developed AD knock-in mouse model to determine (1) how NIHL and AD affects the flow of auditory information from the auditory cortex (ACtx) to the EC, (2) how NIHL and AD affect the time-course of cognitive decline during auditory decision making, and (3) whether NIHL accelerates accumulation of the pathological hallmarks of AD, neuroinflammation, and synaptic degeneration. We expect that NIHL will render the auditory information flow into the EC hyperactive, which will correlate with a diminished ability to remember and discriminate auditory stimuli and an exacerbation of AD neuropathology. By explicitly quantifying how NIHL and AD progression interact at the level of sensory information processing, cognitive function, and pathogenesis, these studies have the potential to unveil a much sought-after causal link between hearing loss and the pathophysiology of AD.

项目摘要 听力损失发生在约80%的65岁以上的成年人中，并且被认为是最严重的原因。 痴呆症的可变风险因素。阿尔茨海默病（AD）是年龄相关性痴呆的最常见形式。 压倒性的最新证据表明，听力损失，AD神经病理学和记忆之间存在关联 功能已知记忆编码需要一个完整的内鼻-海马回路， 严重影响AD。最近的研究，包括我们自己的研究，已经开始梳理解剖学的路线， 听觉信息通过内嗅皮层（EC）到达海马（HPC）。但没有 迄今为止，一项研究已经全面调查了噪声性听力损失（NIHL）如何影响神经回路 完整性，并将这些发现整合到AD中观察到的神经病理学和行为变化中 患者 为了解决这一知识缺口，我们将利用最近开发的AD基因敲入小鼠模型来确定 (1)NIHL和AD如何影响听觉信息从听觉皮层（ACtx）到EC的流动，（2）如何 NIHL和AD影响听觉决策过程中认知功能下降的时程;（3）NIHL是否 加速AD、神经炎症和突触变性的病理标志的积累。 我们预计，NIHL将使听觉信息流进入EC过度活跃，这将与 记忆和辨别听觉刺激的能力减弱以及AD神经病理学恶化。 通过明确量化NIHL和AD进展如何在感觉信息处理水平上相互作用， 认知功能和发病机制，这些研究有可能揭示一个备受追捧的因果关系 听力损失和AD的病理生理学之间的联系。