SYNAPTIC MECHANISMS IN THE AUDITORY SYSTEM

听觉系统中的突触机制

• 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
• 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

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.

禽核细胞核和哺乳动物腹侧耳蜗核中的神经元传递了相锁动作电位的时机，其精度很高。 通过膜水平的各种细胞适应性，它们可以保留时序的能力，这对于这些神经元在声音定位中的关键作用至关重要。 虽然这些神经元长期以来已被GABA能轴突接触，但这种推测的抑制输入的功能知之甚少。 这很重要，部分是因为GABA受体是常见的药理学靶标，并且与多种神经系统疾病有关。 拟议的研究的目的是确定突触发行的GABA如何修改听觉神经纤维产生的信号。 这将使用脑切片的脑切片制剂来完成，其中将夹紧单个细胞，并分别刺激单个细胞夹板，并分别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受体激活来确定GABA释放和突触后GABA动作的机制，同时测量GABAergic突触的突触前钙的积累，探索一种新发现的现象，即在刺激过程中，从突触中释放GABA的GABA释放就会变得异常。 我们还将使用刺激和抑制性纤维的刺激来确定突触如何在突触后，电水平或突触前水平上通过发射机扩散到GABAB亚型的突触前调节受体。 GABA受体激活的动力学将使用化学割礼的神经递质的快速释放来确定，以确定GABA前和突触后作用的相对时间尺度。 这项工作还将研究以下观察结果：突触前GABA受体可以在耳蜗核中具有兴奋性传播的增强作用，显然与归因于GABA的经典抑制作用相反。 拟议的研究将阐明GABA如何促进这些神经元的继电器功能，并为GABA能药物如何改变人类的感觉处理提供新的线索。