Mechanisms Shaping Temporal Integration in the Inferior Colliculus

下丘时间整合的塑造机制

• 批准号: 10747462
• 负责人: Audrey Claire Drotos
• 金额: $ 4.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747462
• 关键词: AMPA Receptors; Address; Auditory; Auditory area; Auditory system; Brain; Brain region; Closure by clamp; Cochlear nucleus; Code; Complex; Data; Endowment; Excitatory Postsynaptic Potentials; Excitatory Synapse; Exhibits; Frequencies; Glutamate Receptor; Human; In Vitro; Inferior Colliculus; Intervention; Kinetics; Knowledge; Literature; Membrane Potentials; Midbrain structure; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Pharmacology; Phase; Play; Population; Process; Property; Research; Rest; Role; Shapes; Site; Slice; Speech; Stimulus; Structure; Synapses; Testing; Thalamic structure; Time; Training; Work; antagonist; auditory pathway; awake; experimental study; hearing impairment; in vivo; insight; optogenetics; patch clamp; phenomenological models; rate of change; receptor; response; sound; tool; vocalization; voltage

Abstract Natural sounds contain rapid fluctuations in the amplitude envelope, and detecting these changes is an im- portant task of the auditory system. Early auditory structures such as the cochlear nucleus primarily encode amplitude modulations (AMs) in sound by phase locking their firing to the AM waveform, while the auditory cor- tex primarily uses changes in firing rate to encode AM modulation frequencies. Located in the middle of the ascending auditory pathway, the inferior colliculus (IC) plays a critical role in transforming the temporal code of the periphery to the rate code that predominates in the thalamus and cortex. However, little is known about the cellular mechanisms that underlie the shift from temporal to rate coding of AM stimuli in the IC. The overall ob- jective of this proposal is to determine how NMDA receptors (NMDARs) contribute to the transition from tem- poral to rate codes in the IC. NMDARs are glutamate receptors that are prominently expressed in the IC and that prolong the time window for synaptic integration due to their slow kinetics compared to AMPA receptors. These properties make NMDARs strong candidates for supporting a temporal to rate code transition. Con- sistent with this, previous work showed that blocking NMDARs flattened firing rate AM tuning curves in the IC while leaving temporal coding intact. Furthermore, while most NMDARs in the brain require depolarization to relieve Mg2+ block, many IC neurons exhibit NMDAR responses at resting potential, which is expected to en- hance their capacity to prolong the time window for synaptic integration. Our preliminary data provide the first molecular mechanism for this phenomenon, showing that many IC neurons express NR2C or NR2D subunits, NMDAR subunits which confer decreased sensitivity to Mg2+ block and enable NMDARs to activate at resting membrane potential. We also found that NR2D subunits are expressed in VIP neurons, a recently identified class of IC principal neurons, providing us a tool to reliably access a population of NR2D-expressing neurons. Our preliminary data show that NR2D-containing NMDARs facilitate synaptic integration in VIP neurons in vitro. We therefore hypothesize that NR2C/NR2D-containing NMDARs facilitate a shift from temporal to rate coding in the IC by enhancing the time window for synaptic integration of phase-locked ascending inputs and transforming those into a rate code. To test this hypothesis, in Aim 1 we will record in vitro from VIP neurons in the IC and use optogenetics, pharmacology, and dynamic clamp experiments to determine how NR2D-contain- ing NMDARs influence synaptic integration. In Aim 2, we will use pharmacology and in vivo recordings in awake mice to test how rate coding for AM stimuli in the IC is shaped by NR2C/NR2D-containing NMDARs. Overall, our results will reveal cellular mechanisms underlying the shift from temporal to rate coding in the IC, which will help us better understand how AMs in sound are encoded in the brain and facilitate better interven- tions for those with hearing loss.

摘要 自然声音在幅度包络中包含快速波动，检测这些变化是一种非常重要的方法。 听觉系统的重要任务。早期的听觉结构，如耳蜗核，主要编码 声音中的幅度调制(AM)通过将它们的激发锁定在AM波形上来实现，而听觉上的调制(AM)是通过将其触发锁定在AM波形上来实现的。 TeX主要使用触发速率的变化来编码AM调制频率。位于中心的 在上行听觉通路中，下丘(IC)在时间编码的转换中起着关键作用 在丘脑和皮质中占主导地位的心率编码的外围。然而，人们对此知之甚少 IC中AM刺激从时间编码到速率编码的细胞机制。总体目标是- 这一建议的目的是确定NMDA受体(NMDAR)如何促进从Tm-Tm到Tm-Tm的转变。 端口到IC中的速率代码。NMDAR是一种谷氨酸受体，在IC和 这延长了突触整合的时间窗口，因为与AMPA受体相比，它们的动力学速度较慢。 这些特性使NMDAR成为支持从时间到速率代码转换的有力候选者。CON- 与此一致的是，以前的工作表明，阻断NMDAR会使IC中的放电频率AM调谐曲线变平 同时保持时间编码完好无损。此外，虽然大脑中的大多数NMDAR需要去极化来 许多IC神经元在静息状态下表现出NMDAR反应，从而解除了对镁离子的阻断，这有望增强NMDAR反应。 增强他们延长突触整合时间窗口的能力。我们的初步数据提供了第一个 这种现象的分子机制表明，许多IC神经元表达NR2C或NR2D亚单位。 NMDAR亚基对镁离子阻断的敏感性降低，并使NMDAR能够在休息时激活 膜电位。我们还发现，NR2D亚单位在VIP神经元中表达，这是最近发现的一种 一类IC主神经元，为我们提供了一种可靠地访问NR2D表达神经元群体的工具。 我们的初步数据显示，含有NR2D的NMDAR促进了VIP神经元的突触整合。 体外培养。因此，我们假设包含NR2C/NR2D的NMDAR促进了从时间到速率的转换 通过增强锁相上升输入的突触积分的时间窗口在IC中编码 将这些代码转换为费率代码。为了验证这一假设，在目标1中，我们将在体外记录 IC并使用光遗传学、药理学和动态钳制实验来确定NR2D-如何包含- ING NMDAR影响突触整合。在目标2中，我们将使用药理学和活体记录 唤醒小鼠，测试IC中AM刺激的速率编码如何由含有NR2C/NR2D的NMDAR塑造。 总体而言，我们的结果将揭示IC中从时间编码到速率编码的潜在细胞机制， 这将帮助我们更好地理解声音中的AM是如何在大脑中编码的，并促进更好的干预- 为听力损失的人做的手术。