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（通过应用程序提供）：使用2个耳朵的听力允许提取包括人类在内的动物（包括人类）在空间中定位声音的声音时序信息，并在复杂的听觉环境中进行全面的通信信号。了解双耳听力系统如何发展对于为有障碍的个体实施治疗至关重要。哺乳动物脑干中的培养基上橄榄（MSO）核构成了两只耳朵的加工组合信息的第一个阶段之一。 MSO神经元能够通过在特定的手段时间差异（ITD）（ITD）响应最大的二进制兴奋，从而检测到2耳的声音到达之间极为微小的时序差异。对MSO神经元的糖抑制输入对于塑造其ITD反应至关重要。在听到发作之前，超努抑制输入均匀分布在MSO神经元的树突和躯体上。听到发作后，抑制作用得到了巨大完善。大多数抑制性输入都被修剪，并且保留的抑制性输入是二进制兴奋的定时，并集中在躯体上。尽管与该重要电路的功能相关，但几乎什么都不了解指导MSO中抑制作用的细胞机制。突触可塑性可能是在经验依赖性过程中维持特定突触的关键。这里提出的工作旨在了解MSO中的抑制性合成可塑性及其在听到发作后如何促进抑制驱动的发展。该项目利用了蒙古语沙鼠的急性脑切片中的电生理和钙成像技术，并结合了对二元听觉经验的体内操纵。 AIM 1将揭示合成可塑性的机制，从而指导MSO中二进制兴奋的抑制驱动的加强和同步。 Preliminary results suggest a model of N-methyl D-aspartate receptor (NMDAR)-dependent inhibitory long-term potential (iLTP) in the MSO in which glutamate, either co-released with glycine or through spilover from adjacent excitement inputs, binds NMDARs and action potential (AP)-driven depolarisation from binary excitement drive rescues the magnesium block. NMDAR激活的基因座和谷氨酸的来源将被确定。 AIM 2试图了解是什么指导了抑制性投入到MSO神经元的体内的发展浓度。在听力的前2周，MSO神经元内固有膜特性的变化减少了AP沉积到树突中的侵袭。我的假设是，树突中的抑制性突触逐渐无法接受ILTP的足够的depolarisis，并且没有这种持续的加固。为了检验这一假设，我将在全向噪声中培养动物，这是一种已知会破坏双耳线索的操纵。然后，我将确定ILTP，内在变化和抑制的体细胞分离是否受到阻碍。这项工作总之将使我们对这一重要的双耳线索处理中心中对经验依赖的发展抑制的发展进行更深入的了解。