A tachykinin precursor 1 medullary circuit promoting rhythmic breathing

Abstract

AbstractRhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBötzinger Complex (preBötC), a region of the medulla, necessary for the generation of rhythmic breathing in mammals. The preBötC is comprised of various neuronal populations expressing neurokinin-1 receptors, the cognate G-protein-coupled receptor of the neuropeptide substance P (encoded by the tachykinin precursor 1 orTac1). Neurokinin-1 receptors are highly expressed in the preBötC and destruction or deletion of neurokinin-1 receptor-expressing preBötC neurons severely impairs rhythmic breathing. Application of substance P to the preBötC stimulates breathing in rodents, however substance P is often associated with nociception and locomotion in various brain regions, suggesting thatTac1neurons found in the preBötC may have diverse functional roles. Here, we aim to characterize the role ofTac1-expressing preBötC neurons in the generation of rhythmic breathingin vivo, as well as motor behaviors. Using a cre-lox recombination approach, we injected adeno-associated virus containing the excitatory channelrhodopsin-2 ChETA in the preBötC region ofTac1-cre mice. Using a combination of histological, optogenetics, respiratory, and behavioral assays, we defined the identity and the role ofTac1preBötC neurons. These neurons are glutamatergic and their stimulation promotes rhythmic breathing in both anesthetized and freely moving/awake animals, but also triggers locomotion and overcomes respiratory depression by opioid drugs. Overall, our study identifies a new population of excitatory preBötC with major role in rhythmic breathing and behaviors.