Influence of T-Stellate Cell Input on Sound Processing in the Inferior Colliculus

摘要：下丘(IC)是听觉系统的中脑中枢，对中枢神经系统的发育具有重要作用。 语音和其他发声的处理。T-星状神经元提供了来自 前腹侧耳蜗核(AVCN)至IC，参与了发声过程 提示，因为它们编码有关声音频率和幅度调制(AM)的信息。然而，如何T- 星状细胞影响特定的中枢神经元群以及它们如何塑造语音和发声编码 在IC中是未知的。研究T-stellate对IC的输入的一个障碍是缺乏分子标记 IC神经元分类。最近，我们通过鉴定两类新的IC神经元克服了这一障碍： 谷氨酸能VIP神经元和GABA能NPY神经元。VIP和NPY神经元加在一起约占55%-75% IC中央核内的星状细胞。使用通道视紫红质辅助的电路映射和 荧光靶向全细胞脑片记录，我们的初步数据显示，VIP和NPY 神经元接受来自T星状细胞的功能性突触输入。有趣的是，兴奋性突触后 传入T-星状神经元的NPY神经元诱发的电位(EPSP)幅度大于VIP诱发的电位 神经元。此外，T-星状终末的光发生激活可以在两个NPY中引起前馈抑制 和VIP神经元，提示T-星状传入可在IC内募集局部抑制回路。去调查 T-星状细胞如何影响IC中的频率调谐和AM选择性，我们将在体内制作单个单元 用抑制化学遗传学方法记录抑制T-星状细胞传入前后的IC神经元 受体hM4Di。在初步实验中，我们已经验证了我们的化学发生方法，表明 HM4Di和兴奋性视在T星状细胞中的共表达使我们能够降低幅度 用hM4Di激动剂对IC神经元中光诱发的EPSP的影响。这项提议的总体目标是 确定T-星状细胞传入NPY和VIP的患病率、动力学和药理学的差异 并确定T-星形输入如何影响体内的频率调谐和AM编码。在目标1中， 我们将确定T-星状细胞对神经肽Y的输入的患病率、短期可塑性和受体药理学 以及利用IC切片上的全细胞记录进行VIP神经元的体外培养。在目标2中，我们将确定T-星形如何 神经元通过选择性抑制T-星形胶质细胞在IC中形成频率调谐和AM编码 化学遗传学，同时记录来自IC神经元的。预期结果将提供直接证据，说明 IC的特定上行输入源支持处理对以下各项非常重要的听觉提示 理解语音和其他发音。

Abstract: The inferior colliculus (IC) is the midbrain hub of the auditory system and is important for the processing of speech and other vocalizations. T-stellate neurons provide the only direct projection from the anteroventral cochlear nucleus (AVCN) to the IC and have been implicated in the processing of vocalization cues since they encode information about sound frequency and amplitude modulations (AM). However, how T- stellate cells influence specific populations of IC neurons and how they shape speech and vocalization coding in the IC is unknown. One barrier to studying T-stellate input to the IC has been a lack of molecular markers for IC neuron classes. Recently, we overcame this barrier by identifying two novel classes of IC neurons: glutamatergic VIP neurons and GABAergic NPY neurons. Together, VIP and NPY neurons represent ~55-75% of stellate cells within the central nucleus of the IC. Using channelrhodopsin assisted circuit mapping and fluorescence-targeted whole cell recordings in brain slices, our preliminary data show that both VIP and NPY neurons receive functional synaptic input from T-stellate cells. Interestingly, the excitatory postsynaptic potentials (EPSPs) evoked by T-stellate input to NPY neurons are larger in amplitude than those evoked in VIP neurons. In addition, optogenetic activation of T-stellate terminals can elicit feedforward inhibition in both NPY and VIP neurons, suggesting that T-stellate afferents can recruit local inhibitory circuits in the IC. To investigate how T-stellate cells influence frequency tuning and AM selectivity in the IC, we will make in-vivo single-unit recordings from IC neurons before and after silencing T-stellate inputs using chemogenetics with the inhibitory receptor hM4Di. In preliminary experiments, we have validated our chemogenetic approach by showing that co-expression of hM4Di and the excitatory opsin Chronos in T-stellate cells enables us to reduce the amplitude of light-evoked EPSPs in IC neurons with an hM4Di agonist. The overall objective of this proposal is to determine differences in the prevalence, dynamics, and pharmacology of T-stellate cell inputs to NPY and VIP neurons, and to determine how T-stellate input influences frequency tuning and AM coding in vivo. In Aim 1, we will determine the prevalence, short-term plasticity, and receptor pharmacology of T-stellate input to NPY and VIP neurons in vitro using whole cell recordings in IC slices. In Aim 2, we will determine how T-stellate neurons shape frequency tuning and AM coding in the IC by selectively inhibiting T-stellate with chemogenetics while recording from IC neurons. The expected results will provide direct evidence about how a specific source of ascending input to the IC supports the processing of auditory cues that are important for understanding speech and other vocalizations.