Circuit Mechanisms for Auditory Processing in the Inferior Colliculus

下丘听觉处理的电路机制

• 批准号: 10188494
• 负责人: Michael Thomas Roberts
• 金额: $ 43.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10188494
• 关键词: Anatomy; Auditory; Auditory Prosthesis; Auditory system; Axon; Brain; Brain Stem; Brain region; Cell Nucleus; Code; Complex; Data; Dendrites; Electrophysiology (science); Excitatory Synapse; Exhibits; Family; Frequencies; Glutamates; Hearing; Inferior Colliculus; Inhibitory Synapse; Intervention; Investigation; Knowledge; Label; Maps; Measures; Midbrain structure; Molecular; Morphology; Neurons; Neurophysiology - biologic function; Noise; Outcomes Research; Output; Pattern; Physiological; Physiology; Play; Population; Process; Property; Research; Role; Sampling; Slice; Sound Localization; Source; Speech; Stimulus; Synapses; Synaptic Transmission; Testing; Time; Training Activity; Vasoactive Intestinal Peptide; Viral; auditory processing; auditory thalamus; base; evidence base; excitatory neuron; experimental study; falls; hearing impairment; improved; in vivo; inhibitory neuron; insight; molecular marker; neural circuit; neuropeptide Y; novel; optogenetics; postsynaptic; postsynaptic neurons; receptive field; response; sound; sound frequency; speech in noise; speech recognition; stellate cell; superior colliculus Corpora quadrigemina; tool; vocalization

Abstract The inferior colliculus (IC) is the midbrain hub of the central auditory system. Although the IC is a critical processing center for speech, vocalizations, and other complex sounds, the neuronal mechanisms underlying computations in the IC remain largely unknown. This gap in knowledge persists because it has proven difficult to reliably identify specific classes of IC neurons. By combining molecular markers with anatomical and physiological measures, we recently overcame this obstacle and have identified two novel classes of IC principal neurons: vasoactive intestinal peptide (VIP) neurons and neuropeptide Y (NPY) neurons. VIP neurons are excitatory, glutamatergic neurons, while NPY neurons are inhibitory, GABAergic neurons. Both VIP and NPY neurons are stellate neurons with dendritic arbors that spread across the tonotopic axis of the central nucleus of the IC (ICc), and both project to multiple brain regions, including the auditory thalamus. Because they can sample input from a range of sound frequencies, it has long been hypothesized that ICc stellate neurons play important roles in sound processing, but the functional roles of stellate neurons have previously been inaccessible. By identifying VIP and NPY neurons, we possess the tools for the first time to selectively target and manipulate an excitatory and an inhibitory class of ICc stellate neurons. The overall objective of this proposal is to establish a functional wiring diagram for the inputs and outputs of VIP and NPY neurons and to determine the differences in how VIP and NPY neurons respond to sounds. To pursue this objective, we will use viral tract tracing, optogenetic circuit mapping, brain slice electrophysiology, and optogenetically-targeted in vivo recordings. In Aim 1, we will identify the ascending sources of auditory input to VIP and NPY neurons and determine how these inputs vary their synaptic strength during trains of activity. In Aim 2, we will identify the long-range targets and terminal arborization patterns of VIP and NPY neurons and determine how synaptic transmission from VIP and NPY neurons influences neurons in the auditory thalamus. In Aim 3, we will test the hypothesis that excitatory VIP neurons and inhibitory NPY neurons differ in their responses to tones and noise and to amplitude- and frequency-modulated sounds, stimuli that represent important features of speech and other vocalizations. The expected outcome of this research is that we will determine for the first time how two classes of ICc stellate neurons, one excitatory and one inhibitory, integrate ascending and descending auditory input, influence long-range postsynaptic targets, and respond to simple and complex sounds. These results will generate evidence-based hypotheses about how ICc stellate neurons contribute to sound processing and will provide a launching point for investigations into the circuit computations that underlie speech and vocalization coding in the midbrain.

抽象的 下丘（IC）是中央听觉系统的中脑枢纽。虽然IC是一个关键 语音、发声和其他复杂声音的处理中心，其背后的神经元机制 IC 中的计算仍然很大程度上未知。这种知识差距仍然存在，因为事实证明这很困难 可靠地识别特定类别的 IC 神经元。通过将分子标记与解剖学和 生理测量方面，我们最近克服了这一障碍，并确定了两类新型 IC 主要神经元：血管活性肠肽（VIP）神经元和神经肽Y（NPY）神经元。 VIP神经元 NPY 神经元是兴奋性谷氨酸能神经元，而 NPY 神经元是抑制性 GABA 能神经元。 VIP 和 NPY 神经元是具有树突乔木的星状神经元，树突乔木遍布中央的音位轴 IC（ICc）核，两者都投射到多个大脑区域，包括听觉丘脑。因为 它们可以对一系列声音频率的输入进行采样，长期以来人们一直假设 ICc 星状 神经元在声音处理中发挥着重要作用，但星状神经元的功能作用以前 已无法访问。通过识别 VIP 和 NPY 神经元，我们第一次拥有了选择性地 靶向并操纵兴奋性和抑制性 ICc 星状神经元。本次活动的总体目标 建议建立 VIP 和 NPY 神经元输入和输出的功能接线图，并 确定 VIP 和 NPY 神经元对声音反应的差异。为了实现这一目标，我们将 使用病毒道追踪、光遗传学电路图谱、脑切片电生理学和光遗传学靶向 体内记录。在目标 1 中，我们将识别 VIP 和 NPY 神经元的听觉输入的上行来源 并确定这些输入在一系列活动期间如何改变其突触强度。在目标 2 中，我们将确定 VIP 和 NPY 神经元的远程目标和末端树枝化模式，并确定突触如何 VIP 和 NPY 神经元的传输影响听觉丘脑的神经元。在目标 3 中，我们将测试 假设兴奋性 VIP 神经元和抑制​​性 NPY 神经元对音调和噪声的反应不同 以及幅度和频率调制的声音，代表语音和语言的重要特征的刺激 其他发声。这项研究的预期结果是我们将首次确定两个 ICc 星状神经元的类别，一类是兴奋性的，一类是抑制性的，整合上行和下行听觉 输入，影响远程突触后目标，并对简单和复杂的声音做出反应。这些结果将 生成关于 ICc 星状神经元如何促进声音处理和意志的基于证据的假设 为研究语音和发声背后的电路计算提供一个起点 中脑编码。