SYNAPTIC MECHANISMS IN THE AUDITORY SYSTEM

鸟类大细胞核和哺乳动物耳蜗腹侧核的神经元通过锁相动作电位的时间非常精确。 它们保持时间的能力是通过膜水平上的各种细胞适应而实现的，并且对于这些神经元在声音定位中的关键作用至关重要。 虽然这些神经元早已被GABA能轴突所接触，但对这种抑制性输入的功能知之甚少。 这一点很重要，因为GABA受体是一种常见的药理学靶点，与各种神经系统疾病有关。 这项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。 这将使用鸡大细胞核的脑切片制备物来完成，其中将对单个细胞进行膜片钳，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受体的激活，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，探索一种新发现的现象，即GABA从突触的释放在刺激序列中变得去激活。 我们还将使用兴奋性和抑制性纤维的刺激，以确定突触如何相互作用，无论是在突触后，电气水平，或在突触前水平通过递质扩散到突触前GABAB亚型的调节受体。 GABA受体激活的动力学将使用化学笼状神经递质的快速释放来确定，以确定GABA的突触前和突触后作用的相对时间尺度。 这项工作还将检查的观察，突触前GABA受体可以有增强作用的兴奋性传输在耳蜗核，显然是在与经典的抑制作用归因于GABA。 这项研究将阐明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的线索。

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.