Hierarchy of the vocalization motor patterning circuits

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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.