Determination of the motor patterning system for murine vocalizations with breathing

小鼠呼吸发声运动模式系统的测定

• 批准号: 10593984
• 负责人: Kevin Yackle
• 金额: $ 35.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593984
• 关键词: Ablation; Address; Anatomy; Animals; Apraxias; Articulators; Behavior; Birds; Birth; Brain; Brain Mapping; Brain Stem; Breathing; Characteristics; Childhood; Classification; Collection; Complex; Crying; Data; Dissection; Distant; Dysarthria; Elements; Enterobacteria phage P1 Cre recombinase; FLP recombinase; Fishes; Foundations; Future; Genetic Code; Goals; Human; In Vitro; Infant; Knowledge; Label; Laryngeal muscle structure; Larynx; Learning; Monitor; Monkeys; Motor; Motor Neurons; Movement; Mus; Muscle; Neonatal; Neurons; Pattern; Periodicity; Preparation; Production; Reproducibility; Respiratory Muscles; Sensory; Slice; Songbirds; Speech; Speech Disorders; Speech Pathology; Stereotyping; Structure; Stuttering; System; Testing; Time; Tongue; Work; autism spectrum disorder; central pattern generator; individuals with autism spectrum disorder; motor behavior; neonatal mice; neural; neural circuit; neuroregulation; novel; optogenetics; programs; respiratory; sound; theories; verbal; vocalization; Ablation; Address; Anatomy; Animals; Apraxias; Articulators; Behavior; Birds; Birth; Brain; Brain Mapping; Brain Stem; Breathing; Characteristics; Childhood; Classification; Collection; Complex; Crying; Data; Dissection; Distant; Dysarthria; Elements; Enterobacteria phage P1 Cre recombinase; FLP recombinase; Fishes; Foundations; Future; Genetic Code; Goals; Human; In Vitro; Infant; Knowledge; Label; Laryngeal muscle structure; Larynx; Learning; Monitor; Monkeys; Motor; Motor Neurons; Movement; Mus; Muscle; Neonatal; Neurons; Pattern; Periodicity; Preparation; Production; Reproducibility; Respiratory Muscles; Sensory; Slice; Songbirds; Speech; Speech Disorders; Speech Pathology; Stereotyping; Structure; Stuttering; System; Testing; Time; Tongue; Work; autism spectrum disorder; central pattern generator; individuals with autism spectrum disorder; motor behavior; neonatal mice; neural; neural circuit; neuroregulation; novel; optogenetics; programs; respiratory; sound; theories; verbal; vocalization

Our speech is composed of rhythmically timed elements, closely associated with syllables. This feature is conserved across the animal kingdom, from fish to songbirds to monkeys, suggesting that the tempo embedded within vocalizations is innately encoded. Indeed, others have hypothesized that the rhythmicity of sound production is created by hardwired neural circuits in the brainstem, but evidence to support this theory is lacking. Vocalizations are produced by the concerted activity of articulator (laryngeal and tongue) and breathing muscles. Moreover, vocalizations must seamlessly integrate with or perhaps even override the breathing rhythm. Given this, we hypothesized, as have others, that if a vocalization motor patterning system existed, it would be anatomically and functionally connected to the neural circuits for breathing in the brainstem. We also hypothesized that this same circuit would intrinsically encode the rhythmicity of syllables within vocalizations. These two concepts - the ability to autonomously pattern a rhythmic behavior - would define such a neural circuit as a vocalization central pattern generator ‘CPG’, the first of its kind. To discovery this predicted vocalization CPG, we have studied the neural control of innate murine neonatal cries, which are analogous to the cries of human infants. We found that murine cries have a stereotyped syllabic structure and motor program. These two features of innate cries suggest an underlying cry CPG. We have found a novel cluster of several dozen brainstem neurons that are required to execute cries and premotor to multiple muscles used in vocalizations. Here, we seek to characterize these neurons to determine if they are indeed a bonified vocalization CPG. First, we will study if these neurons produce an autonomous oscillation as well as the connectivity to correctly pattern the activity of muscles used in vocalizing. And then, we will ectopically activate these neurons to find out if they are sufficient to elicit cries. The significance of this proposal is multifold. First-and-foremost, we will identify and characterize a long-sought vocalization CPG. This forms a foundation to map the brain-wide circuitry used in innate and learned vocalization. Second, we will determine how the vocalization and breathing CPGs interact. An intriguing possibility is that our most vital neural circuit that controls breathing might be overridden. In fact, even how distinct mammalian CPGs cooperate to produce complex behaviors remains poorly understood. And ultimately, this work will enable dissection of the mechanisms of speech pathologies in autism spectrum disorders as well as apraxia, dysarthria, or stutter.

我们的演讲由有节奏的定时元素组成，与音节密切相关。这 从鱼类到歌手再到猴子，整个动物王国都保存了特征 嵌入在发声中的速度是天生编码的。确实，其他人有 假设声音产生的节奏性是由硬线神经回路创造的 脑干，但是缺乏支持该理论的证据。 发声是由旋转器的一致活动（喉和舌头）产生的 和呼吸肌肉。而且，发声必须与 覆盖呼吸节奏。鉴于此，我们和其他人一样假设，如果发声 有运动模式系统存在，它在解剖和功能上连接到中性 呼吸的电路。我们还假设同一电路将 本质上编码声音中音节的节奏性。这两个概念 - 能够自主对节奏行为进行自主的能力 - 将这种神经回路定义为 发声中心模式生成器“ CpG”，这是第一个。 为了发现这种预测的发声CPG，我们研究了先天的神经控制 鼠新生儿哭泣，类似于人类婴儿的哭泣。我们发现那鼠 哭声具有刻板印象的音节结构和运动程序。先天哭泣的这两个特征 建议一个基本的哭泣CpG。我们发现了一个新的数十个脑干的集群 需要对发声中使用的多个肌肉执行哭声和前的神经元。 在这里，我们试图表征这些神经元，以确定它们是否确实是奖励 发声CPG。首先，我们将研究这些神经元是否也产生自主振荡 作为正确模拟发声肌肉的活动的连通性。然后，我们将 通过生态激活这些神经元，以找出它们是否足以引起哭声。 该提案的意义是多重的。首先，我们将确定和 表征长期发声的CPG。这构成了绘制大脑范围的基础 天生和学识渊博的发声中使用的电路。其次，我们将确定发声如何 和呼吸CPG相互作用。一个有趣的可能性是我们最重要的神经回路 控制呼吸可能被覆盖。实际上，即使是不同的哺乳动物CPG合作 产生复杂的行为仍然很糟糕。最终，这项工作将启用 自闭症谱系中语音病理机制的解剖以及 失用，构思障碍或口吃。