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.

抽象的 自然声音的幅度包络包含快速波动，检测这些变化是一项重要的任务。 听觉系统的重要任务。早期的听觉结构，例如耳蜗核，主要编码 通过将其发射锁相到 AM 波形来对声音进行幅度调制 (AM)，而听觉相关 tex 主要使用发射率的变化来编码 AM 调制频率。位于中间 在上行听觉通路中，下丘（IC）在转换听觉的时间编码中起着至关重要的作用 丘脑和皮质中占主导地位的速率代码的外围。然而，人们对此知之甚少 IC 中 AM 刺激从时间编码转变为速率编码的细胞机制。整体OB- 该提案的目的是确定 NMDA 受体（NMDAR）如何促进从温度- 用于评价 IC 中的代码。 NMDAR 是谷氨酸受体，主要在 IC 和 由于与 AMPA 受体相比其动力学较慢，因此延长了突触整合的时间窗口。 这些特性使 NMDAR 成为支持时间到速率代码转换的有力候选者。康- 与此一致的是，之前的工作表明，阻断 NMDAR 会使 IC 中的发射率 AM 调谐曲线变平 同时保持时间编码完整。此外，虽然大脑中的大多数 NMDAR 需要去极化才能 缓解 Mg2+ 阻滞后，许多 IC 神经元在静息电位下表现出 NMDAR 反应，预计这会导致 增强它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 亚基， NMDAR 亚基可降低对 Mg2+ 阻断的敏感性，并使 NMDAR 在静息时激活 膜电位。我们还发现 NR2D 亚基在 VIP 神经元中表达，VIP 神经元是最近发现的 类 IC 主要神经元，为我们提供了可靠地访问表达 NR2D 的神经元群体的工具。 我们的初步数据表明，含有 NR2D 的 NMDAR 促进 VIP 神经元中的突触整合 体外。因此，我们假设包含 NR2C/NR2D 的 NMDAR 促进从时间到速率的转变 通过增强锁相上升输入突触整合的时间窗口来在 IC 中进行编码 将它们转换为费率代码。为了检验这一假设，在目标 1 中，我们将在体外记录 VIP 神经元 IC 并使用光遗传学、药理学和动态钳实验来确定 NR2D-包含- NMDAR 影响突触整合。在目标 2 中，我们将使用药理学和体内记录 唤醒小鼠以测试 IC 中 AM 刺激的速率编码是如何由包含 NR2C/NR2D 的 NMDAR 形成的。 总的来说，我们的结果将揭示 IC 中从时间编码向速率编码转变的细胞机制， 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 对于那些有听力损失的人来说。