A Neural Control Circuit for Cough-Like Defensive Behaviors in Mice

Abstract

Breathing is a vital and complex behavior that rapidly responds to the physiological states and stimuli in the body. Breathing patterns are controlled by the brainstem, which receives constant peripheral sensory information from the lungs and the airway. Respiratory defensive behaviors, such as coughs and expiratory reflexes, disrupt rhythmic respiration as a means of protecting the airway. The function of these reflexes is to remove inhaled particles, pathogens, irritants, or foreign bodies from the respiratory tract by generating a rapid expiratory airflow. A cough is generated by a complex and sequential motor pattern involving three phases: inspiration, compression, and expulsion. Meanwhile, an expiratory reflex lacks an initial inspiration. Often, both reflexes occur intermittently during clinically-defined episodes of coughing, hinting at a shared mechanism underlying these cough-like behaviors. Although these behaviors become excessive under pathological conditions, affecting quality of life, effective anti-tussive medications are lacking. Understanding how sensory stimuli within the body regulate coughs and expiratory reflexes may help to address this gap.

Here, we argue that tachykinin 1 (Tac1) neurons in the nucleus of the solitary tract (NTS) are a key component of the neural circuit that controls cough-like defensive behaviors in mice. First, we show that the NTS, a key hub in the brainstem for processing internal sensory signals and mediating interoceptive processes, contains heterogenous neuronal populations. Activating different neuronal populations via optogenetics within the NTS induced diverse breathing responses, including an ectopic inspiratory peak, apnea, and a sigh. Within these subtypes, activation of Tac1 neurons triggers a specific respiratory behavior. Our detailed characterization of respiratory defensive behaviors, including electromyography (EMG), intrapleural pressure, box flow, video, and audio recordings, reveals that this respiratory behavior is cough-like. The NTS Tac1 neurons are activated during tussive challenges and play an essential role in cough-like behaviors. Optogenetic activation of Tac1 neurons is sufficient in inducing cough-like behaviors, while chronic ablation or acute silencing of these neurons diminishes the cough-like behaviors induced by tussive agents. Using neuronal tracing and optogenetics, we found that these NTS Tac1 neurons directly innervate and coordinate the medullary regions to control sequential phases of cough-like defensive behaviors. In summary, we argue that these Tac1 neurons act as central pattern generators for cough-like defensive behaviors in mice, and that they coordinate the downstream modular circuits to elicit the sequential motor pattern of forceful expiratory responses.