Extratelencephalic contributions to auditory categorization

端脑外对听觉分类的贡献

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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，被认为是最严重的贡献痴呆症的可修改风险因素。阿尔茨海默氏病（AD）是与年龄有关的痴呆症最常见的形式。最近的大量证据表明，听力损失，AD神经病理学和记忆之间存在关联功能。已知记忆编码需要完整的内嗅 - 海马电路，并且该电路为在广告中受到严重影响。最近的研究，包括我们自己的研究，已经开始教授解剖学路线听觉信息需要通过内嗅皮层（EC）到达海马（HPC）。但是，不迄今为止的研究已全面研究了噪声引起的听力损失（NIHL）如何影响神经元电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。为了解决知识的这一差距，我们将利用最近开发的AD Knock-In鼠标模型来确定（1）NIHL和AD如何影响听觉信息从听觉皮层（ACTX）到EC的流动，（2） NIHL和AD会影响听觉决策过程中认知能力下降的时间顺序，（3）NIHL是否是否加速AD，神经炎症和突触变性的病理标志的积累。我们预计NIHL将使听觉信息流入EC多动，这将与记住和区分听觉刺激和AD神经病理学加剧的能力降低。通过明确量化NIHL和AD的进展如何在感觉信息处理级别相互作用，认知功能和发病机理，这些研究有可能揭示出多种有意义的因果关系在听力损失和AD的病理生理之间。