SYNAPTIC MECHANISMS IN THE AUDITORY SYSTEM

听觉系统中的突触机制

基本信息

批准号：
6176947
负责人：
LAURENCE O TRUSSELL
金额：
$ 17.14万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2003-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6176947
关键词：
GABA receptor auditory nuclei calcium flux charge coupled device camera chickens confocal scanning microscopy electrostimulus fluorescent dye /probe gamma aminobutyrate glutamates neurofilament neurotransmitter transport synapses voltage /patch clamp

项目摘要

Neurons in the avian nucleus magnocellularis and mammalian ventral cochlear nucleus passage the timing of phase-locked action potentials with great precision. Their ability to preserve timing is made possible by a variety of cellular adaptations at the membrane level, and is essential for the key role of these neurons in the localization of sound. While these neurons have long been known to be contacted by GABAergic axons, the function of such putatively inhibitory inputs is poorly understood. This is important to clarify in part because GABA receptors are a common pharmacological target and are implicated in a variety of neurological disorders. The goal of the proposed research is to determine how synaptically-released GABA can modify signals generated by auditory nerve fibers. This will be accomplished using a brain slice preparation of the chick nucleus magnocellularis in which individual cells will be patch clamped, and single excitatory and inhibitory presynaptic axons separately stimulated. We will determine the mechanisms of GABA release and postsynaptic GABA action by monitoring of postsynaptic GABAA receptor activation while measuring presynaptic calcium accumulation of GABAergic synapses, exploring a newly discovered phenomenon that GABA release from the synapses becomes desynchronized during stimulus trains. We will also use stimulation of excitatory and inhibitory fibers to determine how the synapses interact, either at the postsynaptic, electrical level, or at the presynaptic level through transmitter diffusion to presynaptic modulatory receptors of the GABAB subtype. The kinetics of activation of GABA receptors will be determined using rapid release of chemically-caged neurotransmitter in order to determine the relative time scales of pre- and postsynaptic actions of the GABA. This work will also examine the observation that presynaptic GABA receptors can have a potentiating effect of excitatory transmission in the cochlear nucleus, apparently at odds with the classical inhibitory role ascribed to GABA. The proposed research will clarify how GABA can facilitate the relay functions of these neurons and provide new clues as to how GABAergic drugs might modify sensory processing in humans.

鸟类大细胞核和哺乳动物腹侧耳蜗核中的神经元非常精确地调节锁相动作电位的时间。它们保持时间的能力是通过膜水平上的各种细胞适应而成为可能的，并且对于这些神经元在声音定位中的关键作用至关重要。虽然人们早就知道这些神经元与 GABA 能轴突接触，但人们对这种假定的抑制性输入的功能知之甚少。澄清这一点很重要，部分原因是 GABA 受体是常见的药理学靶点，并且与多种神经系统疾病有关。本研究的目的是确定突触释放的 GABA 如何改变听觉神经纤维产生的信号。这将通过使用小鸡大细胞核的脑切片制剂来完成，其中单个细胞将被膜片钳，并且单独刺激单个兴奋性和抑制性突触前轴突。我们将通过监测突触后 GABAA 受体激活同时测量 GABA 能突触的突触前钙积累来确定 GABA 释放和突触后 GABA 作用的机制，探索新发现的突触 GABA 释放在刺激序列期间变得不同步的现象。我们还将使用兴奋性和抑制性纤维的刺激来确定突触如何相互作用，无论是在突触后、电水平，还是通过递质扩散到 GABAB 亚型的突触前调节受体在突触前水平。 GABA 受体的激活动力学将通过化学笼式神经递质的快速释放来确定，以确定 GABA 突触前和突触后作用的相对时间尺度。这项工作还将检验突触前 GABA 受体对耳蜗核兴奋性传递具有增强作用的观察结果，这显然与 GABA 的经典抑制作用不一致。拟议的研究将阐明 GABA 如何促进这些神经元的中继功能，并为 GABA 能药物如何改变人类的感觉处理提供新线索。