Fast Inhibition in the Sound Localization Pathway

项目摘要： 声音定位-确定声音在空间中的起源-是听觉系统的主要任务。 虽然在揭示介导声音的基本神经过程方面取得了很大进展， 尽管我们的研究已经定位，但仍然存在重大差距，限制了我们对底层电路的理解。这里我们 重点放在声音定位电路的一个关键组成部分，内侧核所起的作用。 梯形体（MNTB）及其抑制输出。 该提议的首要假设是，快速MNTB抑制对于神经系统的发育是必不可少的。 计算两个声音主要定位核团（内侧和外侧上级橄榄核）的ITD和IID (MSO和LSO）。此外，我们建议MNTB抑制将有足够大的影响， 听觉脑干反应（ABR）的波III的产生，这样MNTB的抑制将 改变这一波。ABR是一种非侵入性地在体内测量脑干神经元活性的方法， 我们关注波III，因为在啮齿动物中，这种波通常与声音中的神经元活动有关。 定位核 为了验证这一假设，我们将光遗传学地操纵MNTB并记录MSO活性以区分 MSO神经元的声音定位的几个竞争模型之间的差异（目的1）。然后我们将从光遗传学角度 操纵MNTB并记录低频LSO活动以研究低频LSO神经元的群体 (Aim 2）。最后，我们将光遗传学抑制MNTB并记录对ABR的反应和影响（目的3）。 这种操作模拟了影响双耳听力的常见听力条件下的类似ABR改变。 总的来说，目的是为了加强我们对听觉中声音定位机制的理解， 脑干，大脑区域，根据不同的声音，执行第一次分离多个声音。 空间位置有许多医学状况，其中该途径的改变导致 患者在嘈杂环境中定位声音和功能的能力下降。更好地理解 健康听觉系统中该回路的神经机制将有助于设计针对这些问题的治疗方法 未来的条件。

Project Summary: Sound localization – determining where in space a sound originates – is a cardinal task of the auditory system. While much progress has been made in uncovering the fundamental neural processes that mediate sound localization, there still remain significant gaps that limit our understanding of the underlying circuit. Here we focus on the role played by one key component of the sound localization circuit, the medial nucleus of the trapezoid body (MNTB), and its inhibitory output. The overarching hypothesis of this proposal is that fast MNTB inhibition is essential for the neural computation of ITDs and IIDs at the two sound main localization nuclei, the medial and lateral superior olive (MSO and LSO, respectively). In addition, we propose that MNTB inhibition will have a sufficiently large effect on the generation of wave III of auditory brainstem responses (ABRs), such that suppression of MNTB will alter this wave. ABRs are a method that non-invasively measure in-vivo the activity of brain stem neurons, and we focus on wave III because in rodents this wave is commonly associated with activity of neurons in the sound localization nuclei. To test the hypothesis, we will optogenetically manipulate MNTB and record MSO activity to discriminate between several competing models of sound localization by MSO neurons (Aim 1). Then we will optogenetically manipulate MNTB and record low-frequency LSO activity to study a population of low-frequency LSO neurons (Aim 2). Finally, we will optogenetically suppress MNTB and record responses and effects on the ABR (Aim 3). This manipulation mimics similar ABR alterations in common hearing conditions affecting binaural hearing. Overall, the aims are designed to enhance our understanding of sound localization mechanisms in the auditory brainstem, the brain area that performs the first separation of multiple sounds from each other based on their spatial location. There are a number of medical conditions in which alterations in this pathway lead to a patient's decreased ability to localize sound and function in a noisy environment. A better understanding of the neural mechanisms in this circuit in the healthy auditory system will help design treatments for these conditions in the future.