PROPOSAL SUMMARY
Coughing is an important respiratory function that protects the airways and the lungs. The cough reflex
can be activated by inhaled particles, pathogens, irritants, or having a lung disease such as asthma or COVID-
19. The brain controls coughing by expelling air from the respiratory system to clear these accumulated
secretions. Coughing often becomes excessive with severe consequences under pathological conditions,
resorting people to seek medical attention. Effective anti-tussive medications are lacking due to the limited
knowledge on the neural circuit controlling cough. In our lab, we recently developed a mouse model to study
the neural pathways for coughing with the genetic and neurogenetic tools available in mice. We identified a
sub-population of neurons within the nucleus tractus solitarius (NTS) that express the neuropeptide gene
tachykinin 1 (Tac1) that are activated during tussive challenges. Photoactivation of these neurons is sufficient
in inducing coughing, while genetic ablation or chemogenetic silencing of these neurons diminishes the coughs
induced by tussive agents. These results reveal the first genetically defined neurons in the brain that mediate
coughing induced by tussive agents. Based on these preliminary results, we hypothesize that the NTS Tac1
neurons are the key cough control center that are activated by the tussive challenge and integrate the
downstream targets in the brain to induce coughing through the SP-NK1R pathway. Two aims are
proposed: (1) investigate the neural dynamics and molecular pathway underlying how NTS Tac1 neurons
respond to coughing (2) identify the downstream cough circuit of the NTS Tac1 neurons. These studies will be
accomplished by integrating activity recording, pharmacology, circuit tracing, and optogenetics to trace the
neural dynamics, the molecular pathways, and the downstream circuits of the NTS Tac1 neurons in coughing.
To understand how these neurons are modulated in pathological conditions, I will examine their real-time
activation during a tussive challenge and define their molecular pathway. To identify the cough circuit, I will
identify the downstream regions of NTS Tac1 neurons and conduct a functional study on these projections.
The successful completion of this project will advance the knowledge of the endogenous central neural circuit
and pathway underlying cough. Furthermore, it will lead to the potential identification of drug targets for
manipulating cough, thereby providing new opportunities for the development of novel therapeutics and better
treatments for those suffering from excessive coughing.