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计时有很高的精度。它们保持计时的能力是通过在膜水平上的各种细胞适应来实现的，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是由GABA能轴突联系的，但这种假定的抑制性输入的功能却鲜为人知。澄清这一点很重要，部分原因是GABA受体是一个常见的药理靶点，与各种神经疾病有关。这项拟议的研究的目标是确定突触释放的GABA如何改变听神经纤维产生的信号。这将通过制备鸡的大细胞核的脑片来完成，在该脑片中，单个细胞将被膜片钳住，单个兴奋性和抑制性突触前轴突被分别刺激。我们将通过监测突触后GABAA受体的激活来确定GABA释放和突触后GABA的作用机制，同时测量GABA能突触的突触前钙积累，探索一个新发现的现象，即在刺激训练过程中突触的GABA释放变得不同步。我们还将使用刺激兴奋性和抑制性纤维来确定突触如何相互作用，无论是在突触后、电水平，还是在突触前水平，通过向GABAB亚型的突触前调制受体的递质扩散。为了确定GABA突触前和突触后活动的相对时间尺度，将通过快速释放化学笼子中的神经递质来确定GABA受体的激活动力学。这项工作还将检查观察到的突触前GABA受体可以增强耳蜗核的兴奋性传递的作用，显然与经典的归因于GABA的抑制作用不同。这项拟议的研究将阐明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.