Measurement and modeling of central auditory processing in aged animals

描述（由申请人提供）：听力缺陷存在于不断增长的数百万老年听众中。一个基本的知识缺口是，由于有限的体内测量和体内反应与其细胞神经基础之间的脱节，人们对受衰老影响最大的声音的中央听觉表征知之甚少。本研究的长期目标是发现老年动物中枢听觉通路中细胞生理学的改变如何引起单个神经元、局部网络和群体水平上的神经表征的改变，以便基于机制假设的听力维持或恢复计划。鉴于这一目标，本提案的目的是将非侵入性包膜跟踪和频率跟踪反应与体内下丘（IC）尖峰反应和局部场电位（LFPs）以及IC神经元的生物物理模型联系起来。我们的中心假设是，许多与年龄相关的听觉缺陷可以通过细胞神经生理学的少数关键变化来解释，例如抑制作用降低，其后果可以通过测量小群IC神经元或大群脑干和IC神经元对适当的非言语和类言语声音的反应来观察。这项研究的基本原理是，很少有人尝试将体内诊断数据与产生异常反应的潜在神经回路联系起来，这阻碍了治疗缺陷的进展。目标1)识别在老年动物中产生异常包络和频率跟随反应的声音和共同声学特征，以架起动物和人类听觉评估的桥梁。目的2)确定IC神经元在衰老过程中尖峰活动和lfp的变化，以及它们与相同声音引起的反应后包膜变化的对应关系。目的3)利用详细的生物物理IC模型重现体内IC反应，并预测幼龄和老年动物对声音的反应，以区分衰老过程中不同的细胞机制。该研究的预期贡献是创建一个“从诊所到渠道”的知识循环，其中动物中枢听觉活动的非侵入性诊断测量与体内单个神经元反应、LFPs和IC神经元的详细机制模型相关联。这一贡献是重要的，因为将体内电生理测量与它们的细胞基础联系起来，创建了一个强大的框架，在这个框架中，迭代地识别导致与年龄相关的中枢性听觉衰退的因素，并快速预测影响这些因素的潜在治疗的后果。拟议的研究是创新的，因为在人群、局部网络和单/多单位水平上对临床和行为相关声音的体内电生理测量是由中枢听觉系统的详细细胞和突触模型提供信息和约束的，而不是抽象的或基于解剖学的模型。这将为每个水平的药物或行为治疗提供目标。

DESCRIPTION (provided by applicant): Auditory deficits are present in a growing population of millions of elderly listeners. A fundamental gap in knowledge is that central auditory representations of the sounds most affected by aging are poorly understood due to limited in vivo measurements and due to a disconnect between the in vivo responses and their cellular neural bases. The long-term goal of this research is to discover how alterations of cellular physiology in the central auditory pathway of aged animals give rise to altered neural representations at the single-neuron, local network and population levels, in order to target hearing maintenance or recovery programs based on mechanistic hypotheses. Given this goal, the objective of this proposal is to link non-invasive envelope-following and frequency-following responses to inferior colliculus (IC) spiking responses and local field potentials (LFPs) in vivo and to biophysical models of IC neurons. Our central hypothesis is that many age-related auditory deficits can be explained by a small number of critical changes in cellular neurophysiology, such as reduced inhibition, whose consequences can be observed in vivo by measuring the activities of small populations of IC neurons or large populations of brainstem and IC neurons in response to appropriate non-speech and speech-like sounds. The rationale for this research is that there have been few attempts to link diagnostic in vivo data to the underlying neural circuitry that generate aberrant responses, which hampers progress towards remedying the deficits. The proposal objective will be addressed by the following aims: Aim 1) Identify the sounds and shared acoustic features that generate aberrant envelope and frequency following responses in aged animals to bridge animal and human auditory assessments. Aim 2) Determine changes in the spiking activities and LFPs of IC neurons during aging and their correspondence to changes in the envelope following responses evoked by the same sounds. Aim 3) Reproduce in vivo IC responses and predict responses to sounds in young and aged animals using detailed biophysical IC models to distinguish between different cellular mechanisms in aging. The expected contribution of the proposed research is to create a "clinic to channels" knowledge loop wherein non-invasive diagnostic measurements of central auditory activity in animals are linked to in vivo single neuron responses, LFPs and detailed mechanistic models of IC neurons. This contribution is significant because connecting in vivo electrophysiological measurements with their cellular bases creates a powerful framework in which to iteratively identify factors that contribute to age-related central auditory decline and predict rapidly the consequences of potential treatments that affect those factors. The proposed research is innovative because in vivo electrophysiological measurements of clinically and behaviorally relevant sounds taken at the population, local network, and single/multiunit levels are informed and constrained by detailed cellular and synaptic models of the central auditory system, rather than by abstract or anatomically based models. This will provide targets for pharmacologic or behavioral therapy at each level.