Synergistic in vivo and in vitro approaches in the MSO

描述(申请人提供)：内侧上橄榄(MSO)的主神经元处理耳间时间差(ITDS)，用于沿水平面定位声音的提示以及检测噪声中的语音和通信信号。尽管人们对了解ITD处理过程背后的电路动力学有着浓厚的兴趣，但令人惊讶的是，可以用来驱动当前双耳听力和MSO功能模型的实验数据很少。这在一定程度上是因为，MSO神经元的生物物理特化是功能作用的核心，使得使用传统的细胞外记录方法在体内记录这些神经元变得异常困难。虽然脑片中MSO神经元的膜片钳记录的出现使得对MSO神经元突触特性的详细研究成为可能，但电路连接的强制性中断阻碍了这些研究准确地再现双耳输入的生理时序和平衡。目前的提议将为弥合体外细胞电生理学方法和体内全动物声学研究之间的概念和技术差距提供第一个明确的努力。首先，我们将使用在体MSO神经元的膜片钳记录，并记录对单耳和双耳刺激的反应。我们将使用细胞内方法来比较IPSI和对侧声刺激的反应在时间、形状和(A)对称性方面的差异。我们将测试这些单耳反应是否允许我们预测相同神经元的双耳反应，我们也将进行测量。其次，为了解释活体实验，我们将开发一种包含听神经以及整个耳蜗核和上橄榄复合体的切片制剂。通过在MSO神经元的全细胞记录中同步刺激一条或两条听神经，我们将在体外再现兴奋性和抑制性突触输入的自然时序，其细节是当前MSO中所有双耳处理模型的基础。还将通过比较对照反应和药物阻断甘氨酸能抑制时诱发的反应来探索抑制的影响和时间。 公共卫生相关性：双耳提示对言语感知和声音定位至关重要，近年来已成为听觉假体刺激范例的关键组成部分。因此，了解双耳信号是如何被大脑处理的，是开发有效的耳聋和其他听力障碍解决方案的先决条件。

DESCRIPTION (provided by applicant): The principal neurons of the medial superior olive (MSO) process interaural time differences (ITDs), cues used for localizing sounds along the horizontal plane as well as detection of speech and communication signals in noise. Despite intense interest in understanding the circuit dynamics that underlie ITD processing, there is surprisingly little experimental data available to drive current models of binaural hearing and MSO function. This is in part due to the fact that the biophysical specializations that are central to MSO neurons< functional role make these neurons unusually difficult to record in vivo with traditional extracellular recording methods. Although the advent of patch-clamp recordings from MSO neurons in brain slices has enabled detailed studies of the synaptic properties of MSO neurons, the obligatory disruption of circuit connections has precluded these studies from accurately reproducing the physiological timing and balance of binaural inputs. The current proposal will provide the first explicit effort to bridge the conceptual and technical gaps between cellular electrophysiological approaches in vitro and whole-animal acoustic investigations in vivo. First, we will employ patch-clamp recordings from MSO neurons in vivo and record responses to both monaural and binaural stimuli. We will use intracellular methods to compare the responses to ipsi- and contralateral acoustic stimulation in terms of their timing, shape, and (a) symmetry. We will test whether these monaural responses allow us to predict the binaural responses of the same neurons, which we will also measure. Second, in order to interpret in vivo experiments, we will develop a slice preparation containing the auditory nerve as well as the entire cochlear nucleus and superior olivary complex. By synchronously stimulating one or both auditory nerves during whole-cell recordings from MSO neurons, we will reproduce in vitro the natural timing of excitatory and inhibitory synaptic inputs, the details of which are the basis for all current models of binaural processing in the MSO. The impact and timing of inhibition will also be explored by comparing control responses to those evoked during pharmacological blockade of glycinergic inhibition. PUBLIC HEALTH RELEVANCE: Binaural cues are critical for speech perception and sound localization, and in recent years have become critical components of stimulation paradigms in auditory prostheses. An understanding of how binaural cues are processed by the brain is thus a prerequisite for the development of effective solutions for deafness and other hearing disorders.