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.

我们的言语由有节奏的计时元素组成，与音节密切相关。 从鱼类到鸣禽再到猴子，这一特征在整个动物界都得到了保留，这表明 事实上，其他人已经对发声中嵌入的节奏进行了编码。 人们认为声音产生的节奏是由硬连线神经回路产生的 脑干，但缺乏支持这一理论的证据。 发声是由发音器官（喉部和舌头）的协调活动产生的 此外，发声必须与甚至呼吸肌肉无缝结合。 鉴于此，我们和其他人一样，追求的是如果发声。 运动模式系统是存在的，它将在解剖学和功能上与神经系统相连 我们还发现，脑干中的呼吸回路也会起作用。 本质上对发声中的音节节奏进行编码——这两个概念。 自主地形成有节奏的行为的能力——将这样的神经回路定义为 发声中心模式发生器“CPG”，同类中的第一个。 为了发现这种预测的发声 CPG，我们研究了先天的神经控制 鼠类新生儿的哭声，与人类婴儿的哭声类似。 哭声具有定型的音节结构和运动程序这两个与生俱来的哭声特征。 我们发现了一个由数十个脑干组成的新簇。 执行发声时使用的多块肌肉的哭声和前运动所需的神经元。 在这里，我们试图表征这些神经元，以确定它们是否确实是骨化的 首先，我们将研究这些神经元是否也产生自主振荡。 作为正确模式发声时使用的肌肉活动的连接。 异位激活这些神经元，看看它们是否足以引起哭泣。 该提案的意义是多方面的。首先，我们将确定并确定这一点。 描述了长期寻求的发声 CPG 的特征，这为绘制全脑图谱奠定了基础。 先天发声和后天发声中使用的电路其次，我们将确定如何发声。 和呼吸 CPG 相互作用的一个有趣的可能性是我们最重要的神经回路。 事实上，即使不同的哺乳动物 CPG 之间的合作方式也可能会被忽视。 产生复杂的行为仍然知之甚少，最终，这项工作将使之成为可能。 剖析自闭症谱系障碍中的言语病理机制以及 失用症、构音障碍或口吃。