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Hierarchy of the vocalization motor patterning circuits

发声运动模式电路的层次结构

基本信息

批准号：
10446346
负责人：
Kevin Yackle
金额：
$ 71.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2024-03-31
项目状态：
已结题

项目摘要

How are complex behaviors that require the coordination of multiple muscle systems produced? How does the brain suddenly turn them “on”? Vocalizations are seemingly simple, yet to occur, ~100 muscles must be coordinated, such as those for articulation (laryngeal and tongue) and breathing. Moreover, vocalizations must seamlessly integrate with or perhaps even override the breathing rhythm. Innate vocalizations occur in multiple behavioral contexts, like mating, and are presumed to be initiated by a gatekeeper, the periaqueductal gray (PAG). These features make vocalization an ideal behavior to answer the two motivating questions posed above. Recently, we have found a novel cluster of several dozen brainstem neurons that are required to execute murine vocalizations, are premotor to and pattern the activity of multiple muscles used in sound production, and produce an intrinsic rhythm that encodes the syllabic structure of vocalizations. Thus, these neurons qualify as a vocalization central pattern generator (CPG), the first of its kind, dubbed the intermediate Reticular Oscillator (iRO). To coordinate with breathing, the iRO reciprocally interacts with the breathing pacemaker, the preBötC. Given that these three brainstem structures for vocalization, the PAG, iRO, and preBötC, are reciprocally connected, is there a hierarchy between them? Do they serve distinct roles in vocalization? For example, does the PAG simply gate when vocalizations occur? Or does it also pattern them? Here, we seek to untangle these relationships. First, we will determine if ectopic activation of the iRO and / or preBötC produces vocalizations. And second, we will determine if vocalizations can be triggered by activation of just the PAG axons within the iRO. We anticipate that the iRO but not preBötC can elicit vocalizations, and the PAG, as a gatekeeper, simply turns “on” the iRO. The significance of establishing the hierarchy of the brainstem vocalization circuitry is multifold. First-and- foremost, by defining the contribution of the iRO or preBötC in vocalization, we will establish the first model system to understand how multiple mammalian CPGs interact to produce complex behaviors. Furthermore, this study will define the premiere circuit to determine how one of our most fundamental rhythms – breathing - is overridden. Second, the definitive establishment of the PAG as a gatekeeper for vocalizations will motivate the mapping of its inputs to define the brain-wide neural circuits driving vocalization. And ultimately, this work, and the work stemming from it, will enable dissection of the mechanisms of speech pathologies in autism spectrum disorders as well as apraxia, dysarthria, or stutter.

需要多个肌肉系统协调的复杂行为是如何产生的？如何大脑突然将它们“打开”？发声看似简单，但要发生，必须协调大约 100 块肌肉，例如那些发音（喉和舌）和呼吸。此外，发声必须与或甚至可能超越呼吸节律。先天发声发生在多种行为环境中，例如交配，并且被认为是由导水管周围灰质（PAG）的看门人发起的。这些功能使发声是回答上述两个激励问题的理想行为。最近，我们发现了一个由数十个脑干神经元组成的新簇，这些神经元需要执行小鼠发声，是用于发声的多块肌肉的前运动并对其活动进行模式化，并且产生编码发声音节结构的内在节奏。因此，这些神经元有资格发声中枢模式发生器（CPG），同类中的第一个，被称为中间网状振荡器（iRO）。为了配合呼吸，iRO 与呼吸起搏器 preBötC 相互交互。鉴于这三种用于发声的脑干结构，PAG、iRO 和 preBötC，是相互关联的是有联系的，他们之间有等级关系吗？它们在发声中发挥不同的作用吗？例如，是否 PAG 只是在发声时进行门控？或者它也对它们进行图案化？在这里，我们试图解开这些关系。首先，我们将确定 iRO 和/或 preBötC 的异位激活是否会产生发声。其次，我们将确定是否可以通过仅激活 PAG 轴突来触发发声。伊罗。我们预计 iRO 而不是 preBötC 可以引发发声，而 PAG 作为看门人，只需 “打开”iRO。建立脑干发声电路的层次结构具有多重意义。首先-和- 最重要的是，通过定义 iRO 或 preBötC 在发声中的贡献，我们将建立第一个模型系统来了解多个哺乳动物 CPG 如何相互作用以产生复杂的行为。此外，这研究将定义首要电路，以确定我们最基本的节奏之一——呼吸——是如何运作的被覆盖。其次，PAG作为发声守门人的明确建立将激励映射其输入来定义驱动发声的全脑神经回路。最终，这项工作，以及由此产生的工作将有助于剖析自闭症谱系中言语病理的机制失用症、构音障碍或口吃等疾病。