Synaptic plasticity and development of inhibition in the medial superior olive

内侧上橄榄突触可塑性和抑制的发展

• 批准号: 9124201
• 负责人: Bradley D Winters
• 金额: $ 6.1万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124201
• 关键词: Action Potentials; Acute; Age; Agreement; Animals; Auditory; Binaural; Binding; Brain; Brain Stem; Calcium; Cell Nucleus; Cells; Chelating Agents; Chloride Ion; Chlorides; Communication; Cues; Dendrites; Detection; Development; Ear; Electrophysiology (science); Ensure; Environment; Fiber; Frequencies; Gerbils; Glutamates; Glycine; Hearing; Housing; Human; Image; Imaging Techniques; Impairment; In Vitro; Individual; Inhibitory Synapse; Injection of therapeutic agent; Lateral; Life; Link; Long-Term Potentiation; Magnesium; Maintenance; Mammals; Medial; Mediating; Membrane; Modeling; N-Methyl-D-Aspartate Receptors; Neurons; Noise; Play; Process; Property; Psychological reinforcement; Receptor Activation; Role; Shapes; Signal Transduction; Slice; Sound Localization; Source; Specificity; Speech; Staging; Synapses; Synaptic plasticity; System; Testing; Time; Work; binaural hearing; critical period; detector; expectation; experience; forging; in vivo; inhibitory neuron; medial superior olive; neuronal cell body; postsynaptic; public health relevance; research study; response; reuptake; segregation; sound; superior olivary nucleus; synaptic depression; synaptogenesis; trapezoid body; two-photon

 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.

 描述（由申请人提供）：使用两只耳朵进行听力可以提取声音定时信息，包括人类在内的动物可以使用这些信息来定位空间中的声音并理解复杂听觉环境中的通信信号。了解双耳听力系统的发展对于实现至关重要。哺乳动物脑干中的内侧上橄榄核（MSO）是处理来自双耳的组合信息的第一阶段之一，能够检测到声音到达之间极其微小的时间差异。两耳的声音通过在特定的耳间时间差 (ITD) 下对双耳兴奋做出最大反应，MSO 神经元上的甘氨酸抑制输入对于形成听觉开始之前的 ITD 反应至关重要，多余的抑制输入均匀分布在树突和体细胞上。 MSO 神经元的听觉出现后，大多数抑制输入都被修剪，而那些与双耳兴奋和集中保持良好同步的输入。尽管与这一重要回路的功能相关，但对于 MSO 中的抑制指导可能是维持体验中一组特定突触的关键的细胞机制几乎一无所知。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促进听力出现后抑制性驱动的发展。该项目利用蒙古人急性脑切片中的电生理学和钙成像技术。沙鼠与双耳听觉体验的体内操纵相结合，将揭示指导 MSO 中双耳兴奋的抑制驱动的加强和同步的突触可塑性机制。 )- MSO 中谷氨酸依赖的抑制性长时程增强 (iLTP)，其中谷氨酸与甘氨酸共同释放或通过相邻兴奋性溢出输入、结合 NMDAR 和双耳兴奋性驱动的动作电位 (AP) 驱动的去极化可缓解镁阻滞。目标 2 旨在了解是什么引导抑制性输入的发育浓度。在听力的前两周，MSO 神经元内在膜特性的变化减少了 AP 去极化对树突的侵入。树突中的抑制性突触逐渐无法获得 iLTP 的足够去极化，并且如果没有这种持续强化，就会被选择性地修剪。为了检验这一假设，我将在全向噪声中饲养动物，这是一种已知会破坏双耳线索的操作，然后我将确定是否有 iLTP。 、内在变化和抑制的躯体分离被延迟，这项工作将使我们更深入地了解这个重要的双耳处理中心的抑制的依赖于经验的发展细化。提示。