Synaptic plasticity and development of inhibition in the medial superior olive

 描述(申请人提供)：使用两只耳朵的听力允许提取声音定时信息，包括人类在内的动物使用这些信息来定位空间中的声音，并在复杂的听觉环境中理解通信信号。了解双耳听力系统是如何发展的，对于实施对有障碍的个人的治疗至关重要。哺乳动物脑干的内侧上橄榄核(MSO)容纳了处理来自两只耳朵的组合信息的第一阶段之一。MSO神经元通过在特定的耳间时间差(ITD)对双耳刺激做出最大反应，能够检测到两只耳朵到达的声音之间的极微小的时间差。对MSO神经元的甘氨酸能抑制输入对其ITD反应的形成至关重要。在听力开始前，额外的抑制输入均匀地分布在MSO神经元的树突和胞体上。在听力开始后，抑制作用被显著地改进。大多数抑制性输入被修剪掉，剩下的输入通过双耳刺激很好地把握时间，并集中在胞体上。尽管与这一重要回路的功能有关，但对指导MSO中抑制作用细化的细胞机制几乎一无所知。突触的可塑性很可能是在一个依赖经验的过程中维持一组特定突触的关键。本研究旨在了解MSO中抑制性突触的可塑性，以及它如何在听力开始后促进抑制性驱动的发展。该项目利用电生理和钙成像技术在蒙古沙土鼠的急性脑片上结合双耳听觉体验的活体操作。目的1揭示突触可塑性的机制，以指导MSO中抑制驱动与双耳兴奋的加强和同步。初步结果提示，在MSO中存在一种依赖N-甲基-D-天冬氨酸受体(NMDAR)的抑制性长时程增强(ILTP)模型，在该模型中，谷氨酸与甘氨酸共同释放或通过相邻兴奋性输入的溢出与NMDAR结合，动作电位(AP)驱动的双耳兴奋性驱动的去极化解除镁阻断。将确定NMDAR激活的位置和谷氨酸的来源。目的2试图了解是什么引导抑制输入的发育集中到MSO神经元的胞体上。在听力的前两周，MSO神经元固有膜特性的改变减少了AP去极化对树突的侵袭。我的假设是，树突中的抑制性突触逐渐不能为iLTP接受足够的去极化，如果没有这种持续的强化，就会选择性地修剪。为了验证这一假设，我将在全方位噪音中饲养动物，这种操纵方式已知会扰乱双耳信号。然后我将确定iLTP、内在变化和抑制的体细胞分离是否被延缓。综上所述，这项工作将使我们更深入地理解抑制在这个重要的双耳线索加工中心中的经验依赖性发展精细化。

 DESCRIPTION (provided by applicant): Hearing using 2 ears allows the extraction of sound timing information that animals, including humans, use to localize sounds in space and comprehend communication signals in complicated auditory environments. Understanding how the binaural hearing system develops is critical for implementing treatments for individuals with impairments. The medial superior olive (MSO) nucleus in the brainstem of mammals houses one of the first stages of processing combined information from both ears. MSO neurons enable detection of extremely minute timing differences between the arrivals of sounds at the 2 ears by responding maximally to binaural excitation at specific interaural time differences (ITDs). Glycinergic inhibitory inputs onto MSO neurons are critical for shaping their ITD responses. Prior to hearing onset, supernumerary inhibitory inputs are evenly distributed over the dendrites and soma of MSO neurons. After hearing onset, inhibition is dramatically refined. Most of the inhibitory inputs are pruned and those that remain are well timed with binaural excitation and concentrated onto the soma. Despite the relevance to the functioning of this important circuit, almost nothing is known about the cellular mechanisms that guide refinement of inhibition in the MSO. Synaptic plasticity is likely to be the key to maintaining a specific set of synapses in an experience-dependent process. The work proposed here seeks to understand inhibitory synaptic plasticity in the MSO and how it contributes to the development of inhibitory drive after hearing onset. This project utilizes electrophysiological and calcium imaging techniques in acute brain slices from Mongolian gerbils combined with in vivo manipulation of binaural auditory experience. Aim 1 will reveal mechanisms of synaptic plasticity that guide the strengthening and synchronization of inhibitory drive with binaural excitation in the MSO. Preliminary results suggest a model of N-methyl D-aspartate receptor (NMDAR)- dependent inhibitory long-term potentiation (iLTP) in the MSO in which glutamate, either co-released with glycine or through spillover from adjacent excitatory inputs, binds NMDARs and action potential (AP)-driven depolarization from binaural excitatory drive relieves the magnesium block. The locus of NMDAR activation and source of glutamate will be determined. Aim 2 seeks to understand what guides the developmental concentration of inhibitory inputs onto the soma of MSO neurons. Over the first 2 weeks of hearing, changes to intrinsic membrane properties of MSO neurons reduce the invasion of AP depolarization into the dendrites. My hypothesis is that inhibitory synapses in the dendrites progressively do not receive sufficient depolarization for iLTP and without this continued reinforcement are selectively pruned. To test this hypothesis, I will rear animals in omnidirectional noise, a manipulation known to disrupt binaural cues. Then I will determine whether iLTP, intrinsic changes, and somatic segregation of inhibition are retarded. Together, this work will give us a deeper understanding of the experience-dependent developmental refinement of inhibition in this important center for processing of binaural cues.