Extratelencephalic contributions to auditory categorization

项目总结 听力损失约80%发生在65岁以上的成年人中，被认为是导致听力损失的最大原因 痴呆症的可改变的危险因素。阿尔茨海默病(AD)是最常见的老年性痴呆症。 最近的大量证据表明，听力损失、AD神经病理和记忆之间存在关联 功能。众所周知，记忆编码需要一个完整的内嗅觉-海马体电路，而这个电路是 在AD中受到严重影响。最近的研究，包括我们自己的研究，已经开始梳理出 听觉信息通过内嗅皮层(EC)到达海马体(HPC)。然而，没有 到目前为止，研究已经全面调查了噪声性听力损失(NIHL)是如何影响神经元回路的 并将这些发现与观察到的AD的神经病理和行为变化结合起来 病人。 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如何影响从听觉皮质(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功能下降的时程；(3)NIHL是否 加速阿尔茨海默病、神经炎症和突触变性的病理特征的积累。 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减弱，阿尔茨海默病的神经病理恶化。 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联系。 听力损失与阿尔茨海默病的病理生理的关系。

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.