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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？这是怎么回事大脑突然把它们“打开”了？发声看似简单，但尚未发生，必须协调约100块肌肉，例如发音(喉咙和舌头)和呼吸。此外，发声必须与或也许甚至超过了呼吸的节奏。先天发声发生在多种行为环境中，比如交配，推测是由守门人中脑导水管周围灰质(PAG)发起的。这些功能使发声是回答上述两个激励性问题的理想行为. 最近，我们发现了一个由几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发声过程中使用的多块肌肉活动的前驱和模式，以及产生一种内在的节奏，编码发声的音节结构。因此，这些神经元被认为是一种发声中枢模式发生器(CPG)，这是第一个被称为中间网状振荡器的发声中枢模式发生器 (Iro)。为了协调呼吸，IRO与呼吸起搏器PrebötC相互作用。鉴于发声的这三种脑干结构，PAG、IRO和PrebötC是相互作用的联系在一起，它们之间是否有等级关系？它们在发声过程中有不同的作用吗？例如，是否当发声发生时，PAG仅仅是门吗？或者，它也会对它们进行模式化？在这里，我们试图解开这些纠结两性关系。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，我们将确定发声是否可以通过激活大脑中的PAG轴突来触发艾罗。我们预计，Iro而不是PrebötC可以引发发声，而PAG作为守门人，只需打开IRO。建立脑干发声回路层次结构的意义是多方面的。首先-而且- 首先，通过定义Iro或PrebötC在发声方面的贡献，我们将建立第一个模型系统，以了解多个哺乳动物CPG如何相互作用，产生复杂的行为。此外，这一点研究将定义首发回路，以确定我们最基本的节奏之一-呼吸-是如何已被覆盖。第二，明确确立PAG作为发声的看门人，将推动对其输入的映射以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使自闭症患者的言语病理机制得以剖析。疾病以及失用症、构音障碍或口吃。