Death by ventilatory failure most frequently occurs in patients with neuromuscular diseases in which there is a loss of respiratory motor neurons. There are currently no significant treatments to prolong or correct for these respiratory deficits. Genetic rodent models of motor neuron loss develop many phenotypes (e.g., dysphagia, limb paralysis, etc.), so in order to study how motor neuron death only impacts respiration and to develop therapeutic interventions, we have developed an inducible model of respiratory motor neuron death. Briefly, rats are intrapleurally injected with cholera toxin B conjugated to saporin (CTB-SAP), which selectively eliminates respiratory motor neurons. Surprisingly, this model displays considerable respiratory plasticity that functions over time to preserve eupneic ventilation. Thus, the fundamental goal of this dissertation is to determine potential strategies that preserve eupneic ventilation following respiratory motor neuron loss. Our data suggest that respiratory plasticity requires different G-protein-coupled receptors and downstream signaling and that the exhibited plasticity is differentially affected by COX1/2-induced inflammation over the course of CTB-SAP induced neuropathology, which may collectively represent one way eupnea is maintained. Additional pilot data indicate diaphragmatic amplitude is decreased in CTB-SAP treated rats, which suggests that extradiaphragmatic muscles (e.g., accessory inspiratory muscles such as the pectoralis minor muscles that can be utilized in disease/injury) are also utilized to maintain eupneic ventilation. Our data suggest that pectoralis minor activity is increased in CTB-SAP rats vs. controls and is further increased in 28d vs. 7d CTBSAP rats. The overall hypotheses of this dissertation are that following CTB-SAP treatment: 1) respiratory plasticity requires differential activation of G-protein-coupled receptor pathways; 2) respiratory plasticity is differentially impacted by COX1/2-induced inflammation; and 3) pectoralis minor muscle amplitude is increased to maintain eupnea. This project will advance our understanding of potential targets (i.e., receptors, inflammatory markers, or muscles) that could be harnessed or stimulated to further preserve and/or improve ventilatory function and quality of life in patients with neuromuscular diseases that are suffering from respiratory motor neuron loss.