A tachykinin precursor 1 medullary circuit promoting rhythmic breathing

Abstract

Rhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBotzinger Complex (preBotC), a region of the medulla, necessary for the generation of rhythmic breathing in mammals. The preBotC 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 or Tac1). Neurokinin-1 receptors are highly expressed in the preBotC and destruction or deletion of neurokinin-1 receptor-expressing preBotC neurons severely impairs rhythmic breathing. Application of substance P to the preBotC stimulates breathing in rodents, however substance P is often associated with nociception and locomotion in various brain regions, suggesting that Tac1 neurons found in the preBotC may have diverse functional roles. Here, we aim to characterize the role of Tac1-expressing preBotC neurons in the generation of rhythmic breathing in 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 preBotC region of Tac1-cre mice. Using a combination of histological, optogenetics, respiratory, and behavioral assays, we defined the identity and the role of Tac1 preBotC 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 preBotC with major role in rhythmic breathing and behaviors.