Synaptic plasticity and development of inhibition in the medial superior olive

 描述（由申请人提供）：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该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。了解双耳听力系统如何发展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级橄榄核（MSO）是处理双耳信息的第一阶段之一。MSO神经元能够通过在特定的耳间时间差（ITD）处最大限度地响应双耳激励来检测声音到达两耳之间的极其微小的时间差。对MSO神经元的甘氨酸能抑制性输入对于形成其ITD反应至关重要。在听觉启动之前，额外的抑制性输入均匀地分布在MSO神经元的树突和索马体上。在听力开始后，抑制作用显著改善。大多数抑制性输入被修剪掉，剩下的那些被双耳刺激很好地定时并集中在索马上。尽管与这一重要回路的功能相关，但对指导MSO抑制细化的细胞机制几乎一无所知。突触可塑性可能是在经验依赖性过程中维持一组特定突触的关键。这里提出的工作旨在了解MSO中的抑制性突触可塑性，以及它如何有助于听力发作后抑制性驱动的发展。本研究利用电生理和钙离子成像技术对蒙古沙鼠急性脑片进行研究，并结合在体双耳听觉体验。目的1揭示MSO中抑制性驱动与双耳兴奋的增强和同步化的突触可塑性机制。初步结果表明，N-甲基D-天冬氨酸受体（NMDAR）依赖性抑制性长时程增强（iLTP）在MSO中的模型，其中谷氨酸，无论是与甘氨酸共同释放或通过溢出从相邻的兴奋性输入，结合NMDAR和动作电位（AP）驱动的去极化从双耳兴奋性驱动解除镁块。将确定NMDAR激活的位点和谷氨酸的来源。目的2试图了解是什么引导抑制性输入集中到MSO神经元的索马上。在听力的前2周，MSO神经元内在膜特性的变化减少了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没有得到足够的去极化iLTP，没有这种持续的强化选择性修剪。为了验证这一假设，我将在全方位噪音中饲养动物，这种操作可以破坏双耳线索。然后，我将确定是否iLTP，内在的变化，和抑制的体细胞分离被推迟。总之，这项工作将使我们更深入地了解在这个重要的中心处理双耳线索的经验依赖的发展完善的抑制。

 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.