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.

项目概要 约 80% 的 65 岁以上成年人出现听力损失，被认为是造成听力损失的最严重原因 痴呆症的可改变危险因素。阿尔茨海默氏病（AD）是与年龄相关的痴呆症的最常见形式。 最近压倒性的证据表明听力损失、AD 神经病理学和记忆之间存在关联 众所周知，记忆编码需要完整的内嗅海马电路，并且该电路是 最近的研究，包括我们自己的研究，已经开始梳理 AD 的解剖学途径。 听觉信息需要通过内嗅皮层 (EC) 到达海马体 (HPC)，但是，没有。 迄今为止的研究已全面调查噪声性听力损失 (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。 为了解决这一知识差距，我们将利用最近开发的 AD 敲入小鼠模型来确定 (1) NIHL 和 AD 如何影响从听觉皮层 (ACtx) 到 EC 的听觉信息流，(2) 如何 NIHL 和 AD 影响听觉决策过程中认知能力下降的时间过程，以及 (3) NIHL 是否 加速 AD、神经炎症和突触变性等病理特征的积累。 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下降，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备受追捧的因果关系 听力损失与 AD 病理生理学之间的关系。