Brainstem control of vocalization and its coordination with respiration

Abstract

Human speech is indispensable for effective communication. However, central or peripheral deficits can lead to the permanent loss of this crucial ability, significantly impacting the quality of life. To help develop future therapies to restore vocal communication capability, we first need a precise understanding of the neural circuits underlying the generation of speech. All animals that can vocalize produce vocal sounds through precise neural control of coordinated actions of multiple laryngeal, orofacial, and respiratory muscles. Here, I utilize mouse vocalization as a model system to investigate the brainstem neural circuits and mechanisms controlling laryngeal muscles—the essential components for phonation. First, I mapped the entire laryngeal premotor circuitry in adult mice. Subsequently, I showed that viral-genetically identified excitatory laryngeal premotor neurons located in the Retroambiguus nucleus (RAmVOC) as both necessary and sufficient for driving vocal-cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAmVOC activation determines the lengths of USV syllables and post-inspiration phases. I further discovered that RAmVOC-neurons receive inhibitory inputs from the respiratory rhythm generator, the preBötzinger complex, and inspiration needs can override RAmVOC-mediated vocal cord closure. Ablating inhibitory synapses in RAmVOC-neurons compromised this inspiration gating of laryngeal adduction, resulting in de-coupling of vocalization and respiration. My dissertation study revealed the hitherto unknown critical circuits for vocal-pattern generation and vocal-respiratory coupling in the brainstem. I further discuss the implications of my work for building neural prosthesis to restore speech in human patients.