Dissecting neural circuits for breathing patterns

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Proposal Summary Breathing is a vital function constantly regulated by the interoceptive signals from the body, and breathing patterns are known to impact emotional and cognitive processes. Breathing patterns with essential pulmonary interoception functions, such as sighing and coughing, are relevant to many pathological conditions, including sleep apnea, sudden infant death syndrome, excessive coughing, COVID-19, and various nervous system disorders, such as panic disorder, phobias, post-traumatic stress disorder, drug abuse, and even brain death. Therefore, there is a critical need to identify the neural mechanisms underlying the interoceptive control of breathing and how they fail under pathological conditions, to develop more effective treatments to breathing abnormalities. Sighing is an augmented breath with a deep, double-size inspiration that is dramatically induced in hypoxia. In contrast, coughing is a protective breathing pattern with a characteristic enlarged expiration phase triggered by tussive agents exposed in the airways. However, the neural circuits underlying these essential and discrete breathing patterns and how the brain interprets and integrates these different interoceptive sensory stimuli are largely unknown. In our preliminary studies, we identified two neuronal populations with distinct gene expression, connectivity, neural activity, and function, in the nucleus of the solitary tract (NTS), the first relay center in the brain that receives interoceptive afferent signals from the visceral organs. These neurons respectively mediate hypoxia induced sighing and tussive challenge induced coughing, two discrete breathing patterns associated with different interoceptive signals. Based on these findings, we propose to test our hypothesis that these two distinct NTS neurons are the key nodes in two segregated interoceptive neural circuits for controlling discrete breathing patterns and for representing these internal states, by receiving distinct afferent inputs and differently activating downstream brain circuits. We will integrate state-of-the-art techniques, including genetic targeting, viral-based neural circuit tracing, activity dependent neuron targeting, optogenetics and chemogenetics, genetic ablation, respiratory physiology, single molecule fluorescent RNA in situ hybridization, and in vivo calcium recording, to identify the neural circuits and pathways underlying these two interoceptive processes in vivo in freely moving mice. By focusing on these two distinct NTS neuron populations and neural circuits, we will delineate the distinct interoceptive afferent pathways from the periphery to the brain, identify the brain regions that mediate sighing and coughing, and define the higher brain regions for interpreting and integrating these distinct interoceptive signals. This work will provide novel molecular and cellular specificity for the interoceptive neural circuits for sighing and coughing respectively, and reveal the organizing principles of the NTS and the brain to ascertain differential interoceptive signals and inputs through the vagal afferent pathways. Furthermore, the proposed studies will also build the foundation for future clinical studies on the role of interoception in neuropathological conditions.