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对锁相动作电位的时间传递具有很高的精度。它们保持时间的能力是通过在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是必不可少的。虽然人们早就知道这些神经元与gaba能轴突联系，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受体是一种常见的药理学靶点，与多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如何改变听神经纤维产生的信号。这将通过鸡大细胞核的脑切片制备来完成，其中单个细胞将被贴片夹住，单个兴奋性和抑制性突触前轴突分别受到刺激。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，探索刺激训练期间突触释放GABA失同步的新发现。我们还将使用兴奋性和抑制性纤维的刺激来确定突触是如何相互作用的，无论是在突触后，电水平，还是在突触前水平，通过递质扩散到GABAB亚型的突触前调节受体。为了确定GABA突触前和突触后作用的相对时间尺度，将利用化学笼化神经递质的快速释放来确定GABA受体的激活动力学。这项工作还将研究突触前GABA受体在耳蜗核中具有兴奋性传递的增强作用，这显然与经典的GABA抑制作用不一致。这项研究将阐明GABA如何促进这些神经元的传递功能，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.