Determination of the motor patterning system for murine vocalizations with breathing

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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.