Measurement and modeling of central auditory processing in aged animals

描述(申请人提供)：听力障碍存在于不断增长的数百万老年听众中。知识中的一个根本差距是，由于体内测量有限，以及体内反应与其细胞神经基础之间的脱节，对受衰老影响最大的声音的中枢听觉表征了解得很少。这项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变化如何引起单个神经元、局部网络和种群水平的神经表征的改变，以便针对基于机械假说的听力维持或恢复计划。鉴于这一目标，本研究的目的是将非侵入性包络跟随和频率跟随反应与活体下丘(IC)尖峰反应和局部场电位(LFP)联系起来，并与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障碍可以由细胞神经生理学中的少量关键变化来解释，例如抑制减少，其后果可以通过测量少量IC神经元或大量脑干和IC神经元对适当的非语音和类似语音的声音的反应在体内观察到。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电路联系起来，这阻碍了弥补缺陷的进展。该提案的目标将通过以下目标来实现：目标1)确定在老年动物中产生异常包络和频率跟随反应的声音和共享声学特征，以架起动物和人类听觉评估的桥梁。目的2)确定中枢神经元放电活动和LFP在老化过程中的变化及其与相同声音引起的包膜跟随反应变化的对应关系。目的3)用详细的生物物理IC模型在幼年和老年动物体内复制IC反应并预测对声音的反应，以区分衰老过程中不同的细胞机制。这项拟议的研究的预期贡献是创建一个“诊所到通道”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、LFP和IC神经元的详细机制模型相关联。这一贡献意义重大，因为将体内电生理测量与其细胞基础联系起来，创建了一个强大的框架，在其中反复确定导致年龄相关中枢听觉下降的因素，并快速预测影响这些因素的潜在治疗的后果。这项拟议的研究具有创新性，因为在群体、局部网络和单个/多单元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限制的，而不是抽象的或基于解剖学的模型。这将为每个级别的药物或行为治疗提供靶点。

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.