The roles of GABAergic and glycinergic inhibition in the adult MNTB

描述（由申请人提供）：斜方体内侧核（MNTB）中的神经元将甘氨酸能抑制投射到多个其他听觉核团，从而将投射发送到其他听觉中心。因此，MNTB直接或间接地控制着大量听觉核团的放电，并参与各种计算，如耳间强度分析、耳间时间分析和许多单耳任务。理解这些过程需要详细了解MNTB中进行的尖峰序列转换，以及有关功能环境的知识，在这种情况下，MNTB神经元可能是沉默的，从而暂停对其他听觉区域的抑制控制。然而，我们对MNTB的理解中的一个令人惊讶的大差距抑制了这种理解水平：MNTB主神经元本身接收大量抑制性输入，其强度与兴奋性输入相匹配，并且能够抑制MNTB中的活动。然而，几乎没有人知道这些抑制性输入，它们的功能特性，它们被激活的条件，以及它们如何与兴奋性输入相互作用以形成MNTB活性。我们建议使用一个组合的体内和体外电生理方法来研究这些抑制性输入的作用。我们的过度假设是MNTB的抑制性输入塑造了神经元对复杂和持续刺激的反应。具体而言，抑制MNTB可以作为一种机制，以提高时间对比度，并锐化响应刺激的开始和瞬态成分的复杂的声音活动。在目标1中，我们建议在体外测试的假设，特定的抑制性输入抑制尖峰MNTB时，某些声音刺激。我们将确定突触特性的抑制性输入在简单和复杂的活动模式，并测试在复杂的和正在进行的刺激模式的处理过程中的兴奋和抑制之间的相互作用。在目标2中，我们将再次使用体外方法关注甘氨酸作为兴奋性传递的调节剂的作用，该调节剂另外使正在进行的活动的起始反应尖锐化。我们将测试的假设，甘氨酸增强兴奋性传输在刺激列车的发作，但抑制兴奋性传输过程中正在进行的活动，从而起到锐化MNTB神经元的复杂和正在进行的活动的发作响应。在目标3中，我们将通过使用体内方法研究GABA能和甘氨酸能输入对MNTB的作用。我们将测试的假设，MNTB的抑制性输入被调谐到最佳频率以上的神经元的相应的最佳兴奋频率，并到达MNTB神经元的潜伏期比相应的兴奋稍长。因此，抑制性输入在体内使对声音刺激的起始响应变尖锐，并且另外抑制MNTB神经元对声音刺激中的频率调制分量（诸如向下）的响应。所有实验均在成年沙鼠（p40及以上）中进行。最近几个月，我们开发了成功记录成年沙鼠MNTB脑切片的技术。我们还开发了从年龄匹配的动物进行体内记录的技术，并通过使用多管电极进行体内药理学操作。此外，我们有一种新型的光敏谷氨酸激动剂，可以通过闪光来控制脑干神经元的放电。该方法将用于研究相当远的抑制源对MNTB的影响。拟议的研究重点是了解一个核，这是听觉脑干神经抑制的最重要来源，因此，结果将对开发治疗不平衡抑制导致的医疗条件，如耳鸣，听源性癫痫发作或老年性耳聋具有重要意义。 公共卫生相关性：斜方体内侧核（MNTB）是一个听觉脑干核团，通过向这些核团发送抑制性投射来控制许多其他听觉中枢的信息处理。然而，我们对MNTB功能的理解存在很大的差距：它的神经元本身接受来自其他大脑区域的强大抑制控制，对此几乎一无所知。我们建议研究这些抑制输入MNTB，并确定其功能作用。这项研究的结果将有助于我们了解一些病理条件和听力障碍，如听源性癫痫发作，耳鸣，或老年人的言语感知能力下降。

DESCRIPTION (provided by applicant): Neurons in the medial nucleus of the trapezoid body (MNTB) project glycinergic inhibition to multiple other auditory nuclei, which in turn send projections to additional auditory centers. Thus, the MNTB controls, directly or indirectly, the firing of a large number of auditory nuclei, and participates in computations as diverse as interaural intensity analysis, interaural time analysis, and a number of monaural tasks. Understanding these processes should require a detailed understanding of spike train transformations performed in the MNTB, and knowledge about functional circumstances, under which MNTB neurons may be silent and thus suspend their inhibitory control over the other auditory areas. However, one surprisingly large gap in our understanding of MNTB inhibits this level of understanding: MNTB principal neurons themselves receive substantial inhibitory inputs, which match the excitatory inputs in strength, and which are capable of suppressing activity in the MNTB. However, virtually nothing is known about these inhibitory inputs, their functional properties, the conditions under which they are activated, and how they interact with the excitatory inputs to shape MNTB activity. We propose to use a combined in-vivo and in-vitro electrophysiology approach to study the role of these inhibitory inputs. Our over-arching hypothesis is that inhibitory inputs to the MNTB shape the neuron's responses to complex and ongoing stimuli. Specifically, inhibition to MNTB may act as a mechanism to enhance temporal contrast, and sharpen responses to stimulus onset and transient components of complex sound activity. In aim 1 we propose to test in-vitro the hypothesis that specific inhibitory inputs suppress spiking in MNTB when certain sound stimuli are presented. We will determine the synaptic properties of the inhibitory inputs in response to simple and complex activity patterns, and test the interaction between excitation and inhibition during the processing of complex and ongoing stimulus patterns. In aim 2 we will focus, again with an in-vitro approach, on the role of glycine as a modulator of excitatory transmission that additionally sharpens onset responses of ongoing activity. We will test the hypothesis that glycine enhances excitatory transmission at the onset of stimulus trains, but depresses excitatory transmission during ongoing activity and thus acts to sharpen the onset response of MNTB neurons to complex and ongoing activity. In aim 3 we will investigate the role of GABAergic and glycinergic inputs to MNTB by using an in-vivo approach. We will test the hypothesis that inhibitory inputs to MNTB are tuned to best frequencies above the neuron's corresponding best excitatory frequency, and arrive at MNTB neurons with a slightly longer latency than the corresponding excitation. Thus, inhibitory inputs sharpen onset responses to sound stimuli in- vivo, and additionally suppress responses in MNTB neurons to frequency modulated components in sound stimuli, such as downward. All experiments will be performed in adult gerbils (p40 and older). In recent months we developed the techniques to successfully record from MNTB brain slices prepared from adult gerbils. We also developed the techniques to perform in-vivo recordings from age-matched animals, and perform pharmacological manipulations in-vivo by using multibarrel electrodes. Furthermore, we have a novel light-sensitive glutamate agonists at our disposal that allows for flashes of light to control brainstem neuronal firing. This method will be used to study the impact of fairly distant sources of inhibition to the MNTB. The proposed studies focus on understanding a nucleus that is the most important source for neural inhibition to the auditory brain stem, and the results will thus be significant for developing treatments for medical conditions resulting from unbalanced inhibition, such as tinnitus, audiogenic seizures, or presbycusis. PUBLIC HEALTH RELEVANCE: The medial nucleus of the trapezoid body (MNTB) is an auditory brain stem nucleus that controls information processing in many other auditory centers by sending inhibitory projections to these nuclei. However, there is a large gap in our understanding of the functioning of the MNTB: Its neurons themselves receive powerful inhibitory control from other brain areas, about which almost nothing is known. We propose to study these inhibitory inputs to MNTB and determine their functional role. The results from the research project will help our understanding of a number of pathological conditions and hearing impairments such as audiogenic seizures, tinnitus, or a decline in speech perception among the elderly.