Mechanisms Shaping Temporal Integration in the Inferior Colliculus

摘要 自然的声音包含振幅包络的快速波动，检测这些变化是一个重要的过程。 听觉系统的重要任务。早期的听觉结构，如耳蜗核， 振幅调制（AM）的声音相位锁定其发射的AM波形，而听觉cor. 特克斯主要使用发射率的变化来编码AM调制频率。酒店位于市中心。 在听觉上行通路中，下丘（IC）在转换听觉时间编码中起着关键作用。 在丘脑和皮层中占主导地位的速率代码的外围。然而，人们对此知之甚少。 在IC中AM刺激从时间编码向速率编码转变的细胞机制。总体上，Ob- 本提案的目的是确定NMDA受体（NMDARs）如何促进从tem- 与IC中的速率代码相对应。NMDAR是谷氨酸受体，其在IC中显著表达， 与AMPA受体相比，由于其缓慢的动力学，延长了突触整合的时间窗口。 这些属性使得NMDAR成为支持时间到速率代码转换的强候选者。逆 与此相一致，以前的工作表明，阻断NMDAR使IC中的放电率AM调谐曲线变平 同时保持时间编码不变。此外，虽然大脑中的大多数NMDAR需要去极化， 解除Mg~（2+）阻滞，许多IC神经元在静息电位下表现出NMDAR反应，这有望增强IC神经元的NMDAR反应。 增强其延长突触整合时间窗的能力。我们的初步数据提供了 这一现象的分子机制，表明许多IC神经元表达NR2C或NR2D亚基， NMDAR亚基，其赋予对Mg 2+阻断的降低的敏感性并使NMDAR能够在静息时激活 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新的神经元表达。 类IC主要神经元，为我们提供了一个工具，可靠地访问NR2D表达神经元的人口。 我们的初步数据表明，NR2D的NMDAR促进VIP神经元的突触整合， 体外因此，我们假设，NR2C/NR2D的NMDAR促进了从时间到速率的转变， - 通过增强用于锁相上升输入的突触整合的时间窗口来在IC中编码，以及 将其转换为费率代码。为了验证这一假设，在目标1中，我们将在体外记录来自VIP神经元的 IC和使用光遗传学，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刺激的速率编码如何通过含有NR2C/NR2D的NMDAR成形。 总的来说，我们的研究结果将揭示IC中从时间编码到速率编码转变的细胞机制， 这将帮助我们更好地了解声音中的AM如何在大脑中编码，并促进更好的干预， 对于听力损失的人来说，

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.