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

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.

我们的语言是由有节奏的时间元素组成的，与音节密切相关。这 从鱼类到鸣禽再到猴子，这一特征在动物界都是保守的，这表明 声音中的节奏是天生编码的。事实上，其他人 假设声音产生的节奏性是由硬连线的神经回路创造的， 脑干，但缺乏证据支持这一理论。 发声是由发音器官（喉和舌）的协调活动产生的 和呼吸肌此外，发声必须无缝集成，甚至可能是 控制呼吸节奏鉴于此，我们假设，就像其他人一样，如果发声 如果运动模式系统存在，它将在解剖学和功能上与神经元连接， 脑干中的呼吸回路我们还假设，同样的电路 内在地编码发音中音节的节奏性。这两个概念- 自主模式的节奏行为的能力-将定义这样的神经回路作为一个 发声中枢模式发生器"CPG"，这是同类产品中的第一个。 为了发现这种预测发声的CPG，我们研究了先天性的 小鼠新生儿的哭声，类似于人类婴儿的哭声。我们发现老鼠 哭声有固定的音节结构和运动程序。这两个与生俱来的哭声特征 暗示着潜在的呐喊CPG我们发现了一个由几十个脑干 这些神经元是执行哭泣所需的，而运动前区则是发声所需的多块肌肉。 在这里，我们试图描述这些神经元，以确定他们是否确实是一个bonified 发声CPG。首先，我们将研究这些神经元是否也产生自主振荡 作为连接正确模式的肌肉活动用于发声。然后我们会 异位激活这些神经元，以确定它们是否足以引起哭泣。 这一建议的意义是多方面的。首先，我们将确定和 描述了一个长期寻求发声CPG。这为绘制全脑范围的 用于先天和后天发声的电路。其次，我们将确定如何发声 和呼吸的CPG相互作用。一个有趣的可能性是，我们最重要的神经回路， 控制呼吸可能会被覆盖。事实上，即使是不同的哺乳动物CPG如何合作， 产生复杂的行为仍然知之甚少。最终，这项工作将使 剖析自闭症谱系障碍的言语病理机制， 失用症构音障碍或口吃