The roles of GABAergic and glycinergic inhibition in the adult MNTB

GABA 能和甘氨酸能抑制在成人 MNTB 中的作用

• 批准号: 8468160
• 负责人: Achim Klug
• 金额: $ 35.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468160
• 关键词: Acute; Adult; Age; Animals; Area; Auditory; Auditory area; Brain; Brain Stem; Cell Nucleus; Cells; Complex; Data; Depressed mood; Distant; Elderly; Electrodes; Electrophysiology (science); Frequencies; Gerbils; Glutamate Agonist; Glycine; In Vitro; Knowledge; Lateral lemniscus; Light; Measures; Medial; Medical; Mental Depression; Methods; Neural Inhibition; Neurons; Output; Pattern; Physiological; Play; Preparation; Presbycusis; Process; Property; Recruitment Activity; Research Project Grants; Role; Shapes; Slice; Sound Localization; Source; Speech Perception; Stimulus; Strychnine; Synapses; Techniques; Testing; Time; Tinnitus; Training; audiogenic seizure; auditory nuclei; hearing impairment; in vitro testing; in vivo; information processing; novel; patch clamp; presynaptic; research study; response; sound; synaptic depression; transmission process; trapezoid body; vocalization

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.

描述（由申请人提供）：梯形体（MNTB）的内侧核中的神经元项目甘氨酸能抑制对其他多个听觉核，进而将预测发送给其他听觉中心。因此，MNTB直接或间接地控制了大量听觉核的触发，并参与了像耳间强度分析，室内时间分析和许多单声道任务一样多样化的计算。了解这些过程应需要对MNTB中执行的尖峰火车转换的详细了解，以及对功能环境的了解，在该情况下，MNTB神经元可能会保持沉默，从而暂停其对其他听觉领域的抑制作用。然而，在我们对MNTB的理解中，一个令人惊讶的差距抑制了这种理解水平：MNTB主神经元本身获得了实质性的抑制输入，这些输入与强度的兴奋性投入匹配，并且能够抑制MNTB的活性。但是，实际上，这些抑制性输入，它们的功能特性，激活的条件以及它们如何与兴奋性输入相互作用以塑造MNTB活性。我们建议使用合并的体内和体外电生理学方法来研究这些抑制性输入的作用。我们的规范假设是，对MNTB的抑制投入塑造了神经元对复杂和持续刺激的反应。具体而言，对MNTB的抑制可能是增强时间对比度的一种机制，并提高对刺激发作和复杂声音活动的瞬态成分的响应。在AIM 1中，我们建议在体外测试一个假说，即当提出某些声音刺激时，特定的抑制输入会抑制MNTB中的尖峰。我们将根据简单和复杂的活性模式来确定抑制性输入的突触性能，并在处理复杂和正在进行的刺激模式过程中测试激发与抑制之间的相互作用。在AIM 2中，我们将再次以一种体外方法为重点，将甘氨酸作为兴奋性传播的调节剂的作用，从而促进了正在进行的活动的发作反应。我们将检验以下假设：甘氨酸在刺激训练开始时增强兴奋性传播，但在持续活动期间抑制兴奋性传播，从而促进MNTB神经元对复杂活动和持续活动的开始反应。在AIM 3中，我们将通过使用体内方法来研究MNTB的GABA能和甘体能输入的作用。我们将测试以下假设：对MNTB的抑制输入被调整为高于神经元相应的最佳兴奋频率的最佳频率，并到达延迟略长的MNTB神经元，而不是相应的激发。因此，抑制性输入增强了对声刺激体内的发作反应，并抑制了MNTB神经元对声音刺激（例如向下）中频率调制组件的响应。所有实验都将在成年的沙鼠（P40及以上）中进行。近几个月来，我们开发了从成年gerbil制备的MNTB脑切片中成功记录的技术。我们还开发了从年龄匹配的动物中执行体内记录的技术，并使用多辅助电极进行药理学操作。此外，我们可以使用一种新型的光敏谷氨酸激动剂，可允许光线闪烁以控制脑干神经元发射。该方法将用于研究相当远的抑制源对MNTB的影响。拟议的研究集中于理解对听觉脑干神经抑制的最重要来源的核，因此，结果对于开发因抑制不平衡的抑制作用，例如耳鸣，听觉性癫痫发作或presbycusis而导致的医疗状况的治疗非常重要。