We must inspire before we expire

Abstract

For mammals, breathing is essential for life and is composed of three phases: inspiration, postinspiration, and active expiration. The networks that generate the three phases are distributed bilaterally and rostrocaudally along the ventral lateral medulla of the brainstem, and are collectively referred to as the ventral respiratory column (VRC). Previous to this work, independent rhythmogenic networks had been identified and characterized for the generation of inspiration, the preBötzinger complex (preBötC), and active expiration, the lateral parafacial nucleus (pFL), in rodents. For decades, models and theories have hypothesized that a region called the Bötzinger Complex (BötC), composed primarily of inhibitory, expiratory interneurons, was responsible for the generation of postinspiration. However, this dissertation describes the discovery of a novel, excitatory, rhythmogenic network, termed the postinspiratory complex, or PiCo, that we have shown to be both necessary and sufficient for the generation of postinspiratory vagal motor output. Techniques including in vitro slice electrophysiology (including a new horizontal brain stem preparation), immunohistochemistry, optogenetics, and in vivo electrophysiology were utilized to characterize the PiCo network. Data herein demonstrate that PiCo neurons co-express both glutamate and acetylcholine and are located immediately dorsomedial to the rostral nucleus ambiguus and caudal to the facial nucleus. The PiCo rhythm is stimulated by norepinephrine and selectively inhibited by both the inhibitory neuropeptide, somatostatin, and the mu-opioid agonist, DAMGO. While the preBötC and PiCo rhythms are dependent on non-NMDA excitatory mechanisms, they both exert a mutual inhibitory influence on each other. Isolated in a transverse slice, the PiCo functions as an independent rhythm generator. We hypothesize that PiCo circuitry is involved in mediating postinspiratory behaviors such as vocalization, swallowing and coughing. Higher cortical brain regions likely influence PiCo neurons via pontine nuclei and the periaqueductal gray (PAG). Failure to coordinate breathing with swallowing or coughing can lead to aspiration pneumonia, the leading cause of death in several neurodegenerative disorders including Alzheimer’s Disease, Parkinson’s Disease, and dementia. PiCo networks could also be involved in the pathology of obstructive sleep apnea. Further work is required to determine PiCo’s role in a variety of behaviors and disorders, and to establish whether PiCo neurons could serve as a future therapeutic target.