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Presynaptic GABA-A receptor activation in auditory brainstem axon terminals

听觉脑干轴突末梢突触前 GABA-A 受体激活

基本信息

批准号：
8600166
负责人：
Catherine Jeanne Chalenski Weisz
金额：
$ 5.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600166
关键词：
Action Potentials Animals Area Auditory Axon Brain Brain Stem Brain region Calcium Calcium Signaling Cell Nucleus Cells Characteristics Cochlear nucleus Contralateral Detection Development Ear Electron Microscopy Electrophysiology (science)Fluorescent Dyes Frequencies GABA Receptor GABA-A Receptor Generations Glutamates Glycine Head Hearing Hearing problem Hereditary Disease Human Image Imaging Techniques Individual Injury Investigation Ipsilateral Lasers Light Location Measures Medial Mediating Mus Neurons Neurotransmitters Pathway interactions Pattern Physiologic pulse Population Presynaptic Receptors Presynaptic Terminals Probability Process Receptor Activation Research Rodent Role Signal Transduction Slice Sound Localization Staging Stereotyping Stimulus Subcellular structure Synapses Techniques Testing Time Whole-Cell Recordings age related gamma-Aminobutyric Acid insight lateral superior olive neuron development neuronal cell body neurotransmitter release novel optogenetics postnatal postsynaptic presynaptic promoter public health relevance receptor research study response sound synaptogenesis therapeutic target tool trapezoid body two-photon vesicular GABA transporter

项目摘要

DESCRIPTION (provided by applicant): The neurons of the lateral superior olive (LSO) in the auditory brainstem receive sound information from both ears. Inputs from the ipsilateral ear are via the cochlear nucleus, which gives rise to an excitatory, glutamatergic projection to the LSO. Inputs from the contralateral ear project to the contralateral cochlear nucleus, then through the medial nucleus of the trapezoid body (MNTB), a group of neurons that convert the glutamatergic signal to an inhibitory, glycinergic projection. The combination of inputs from the two ears determines the ability of LSO neurons to compute the location of sound in space around the head. Early in development the MNTB neurons also release the neurotransmitters GABA and glutamate. The purpose of these neurotransmitters in the proper structural development of neurons from the two ears is not very well understood. If glutamate is absent from the MNTB neurons, it has been shown that there is an improper refinement of patterns of neurons from the two ears that encode the same frequency onto a single LSO neuron. Less is known about the function of GABA in these synapses, but it has been shown that GABA release can cause a calcium rise in the LSO neurons, which may be important for formation of synapses between the neurons. This proposal aims to study the role of GABA in development of the projections from the MNTB to the LSO. Experiments will be performed in brain slices from mice containing both MNTB neurons and their projections to LSO neurons. Techniques will include whole-cell electrophysiology and 2-photon imaging to measure the patterns of activity in neurons when GABA signaling is altered pharmacologically. Tools including fluorescent dyes that measure changes in calcium signaling (indicative of cellular activity) and 'optogenetic' tools that allow stimulation of individual neurons using laser light will be used. The proposal also includes electron microscopy experiments to investigate the subcellular structures at the synapses between MNTB and LSO neurons in order to measure how GABA receptors are involved in the proper formation of synapses between the MNTB and LSO. This research will also have implications for investigation of GABA signaling in other brain regions. Research into the proper formation of neuronal circuits that encode sound localization is crucial for a greater understanding of hearing, both in animals and in humans. Understanding how neurons properly connect in developmental stages guides understanding of what can go wrong in situations in which normal hearing is compromised through aberrant development or through injury. A full understanding of the complexity of the perception of sound will guide refined therapies for treatment of hearing disorders.

描述（申请人提供）：听觉脑干侧上橄榄（LSO）的神经元接收来自双耳的声音信息。来自同侧耳的输入通过耳蜗核，引起兴奋的谷氨酸能投射到LSO。来自对侧耳的输入投射到对侧耳蜗核，然后通过梯形体内侧核（MNTB），一组神经元将谷氨酸能信号转化为抑制性甘氨酸能投射。来自两只耳朵的输入的组合决定了LSO神经元计算声音在头部周围空间位置的能力。在发育早期，MNTB神经元也释放神经递质GABA和谷氨酸。这些神经递质在两耳神经元正常结构发育中的作用尚不清楚。如果MNTB神经元中没有谷氨酸，则表明来自两只耳朵的神经元模式存在不适当的细化，这些神经元将相同的频率编码到单个LSO神经元上。目前对GABA在这些突触中的功能知之甚少，但已经证明，GABA的释放可以引起LSO神经元中钙的升高，这可能对神经元之间突触的形成很重要。本提案旨在研究GABA在从MNTB到LSO的预测发展中的作用。实验将在含有MNTB神经元及其向LSO神经元投射的小鼠脑切片中进行。技术将包括全细胞电生理学和双光子成像，以测量GABA信号在药理学上改变时神经元的活动模式。包括测量钙信号变化（指示细胞活动）的荧光染料和允许使用激光刺激单个神经元的“光遗传学”工具在内的工具将被使用。该建议还包括电子显微镜实验，以研究MNTB和LSO神经元之间突触的亚细胞结构，以测量GABA受体如何参与MNTB和LSO之间突触的正确形成。这项研究也将对其他脑区GABA信号的研究产生影响。研究编码声音定位的神经回路的正确形成，对于更好地理解动物和人类的听觉至关重要。了解神经元在发育阶段如何正确连接，有助于理解在正常听力因异常发育或损伤而受损的情况下可能出现的问题。对声音感知的复杂性的充分理解将指导对听力障碍的精确治疗。