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: 8187830
• 负责人: Achim Klug
• 金额: $ 37.46万
• 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/8187830
• 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. 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.

描述（由申请人提供）：梯形体内侧核（MNTB）的神经元向多个其他听核投射甘氨酸能抑制，这些听核反过来向其他听觉中心发送投射。因此，MNTB直接或间接地控制着大量听觉核的激活，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在MNTB中执行的spike train转换，以及关于MNTB神经元可能沉默的功能环境的知识，从而暂停对其他听觉区域的抑制控制。然而，在我们对MNTB的理解中，一个令人惊讶的巨大差距抑制了这种理解水平：MNTB主神经元本身接受大量抑制性输入，这些抑制性输入在强度上与兴奋性输入相匹配，并且能够抑制MNTB中的活性。然而，实际上对这些抑制性输入、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活性一无所知。我们建议使用体内和体外联合电生理学方法来研究这些抑制输入的作用。我们的首要假设是，对MNTB的抑制性输入塑造了神经元对复杂和持续刺激的反应。具体来说，对MNTB的抑制可能是增强时间对比的机制，并增强对刺激开始和复杂声音活动的瞬态成分的反应。在目标1中，我们建议在体外测试特定抑制输入抑制MNTB尖峰的假设，当某些声音刺激出现时。我们将确定对简单和复杂活动模式的抑制输入的突触特性，并测试在复杂和持续刺激模式的处理过程中兴奋和抑制之间的相互作用。在目标2中，我们将再次以体外方法关注甘氨酸作为兴奋传递的调节剂的作用，该调节剂可以额外地增强正在进行的活动的发病反应。我们将验证甘氨酸在刺激训练开始时增强兴奋性传递，但在持续活动中抑制兴奋性传递，从而增强MNTB神经元对复杂和持续活动的开始反应的假设。在目标3中，我们将使用体内方法研究gaba能和甘氨酸能输入对MNTB的作用。我们将测试一个假设，即对MNTB的抑制性输入被调谐到高于神经元相应的最佳兴奋频率的最佳频率，并以比相应兴奋稍长的延迟到达MNTB神经元。因此，抑制性输入增强了体内对声音刺激的反应，并抑制了MNTB神经元对声音刺激中频率调制成分的反应，例如向下。所有实验将在成年沙鼠（40岁及以上）中进行。最近几个月，我们开发了从成年沙鼠制备的MNTB脑切片中成功记录的技术。我们还开发了对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在体内进行药理学操作。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听觉脑干神经抑制的最重要来源核，因此结果将对开发由不平衡抑制引起的医疗条件的治疗具有重要意义，例如耳鸣，听源性癫痫或老年性耳聋。