Postinspiratory complex: a third excitatory respiratory oscillator

Abstract

Mammalian respiration consists of three phases: (1) inspiration, (2) an early phase of expiration, postinspiration, and (3) a late phase of expiration. Two excitatory oscillators have been proposed for the generation of inspiration and active expiration, a conditional expiration that occurs during the late expiratory phase. However, the cellular and circuit mechanisms underlying the generation of postinspiration are largely unknown. Here we describe a third, previously undiscovered excitatory rhythm generator, the Postinspiratory Complex, or PIC, located immediately caudal to the facial nucleus and just medial and dorsal to the rostral‐most portion of the nucleus ambiguus. In this study a variety of in vitro and in vivo approaches are employed to demonstrate that this rhythmogenic kernel generates activity in the postinspiratory phase. Immunohistochemical and optogenetic techniques are utilized to reveal that PIC neurons co‐express acetylcholine and glutamate. Differential responses to neuromodulators and a distinct anatomical location distinguish the PIC from other described respiratory oscillators. Inhibitory interactions between this rhythmogenic network and the preBötzinger Complex, the network responsible for generating inspiration, establish the relative timing, but are not responsible for the generation of the burst underlying inspiratory and postinspiratory activity. Light stimulation of cholinergic PIC neurons in Chat‐cre:Ai27 mice evokes postinspiratory vagal activity in vivo that can reset the inspiratory rhythm. We therefore propose that the three phases of mammalian breathing are generated by three excitatory rhythmogenic medullary networks that are coordinated by inhibitory mechanisms.Support or Funding InformationNIH NS087828‐01NIH HL107084‐01