PROJECT SUMMARY: Inflammation of the central nervous system (CNS) develops in both systemic infection as well as sterile lung injury. This neuro-inflammation mirrors systemic inflammation and affects the neural control of respiration. We have published that peripheral inflammation evokes neuro-inflammation, decreases synaptic efficacy of vagal sensory feedback and increases the predictability of ventilatory pattern variability (VPV). Thus, we have an overall perspective of the effects of systemic inflammation on respiratory control at molecular and functional levels, but the effects at the level of the respiratory network activity remain obscure. Our hypothesis is that brainstem neuro-inflammation alters synaptic strengths in the respiratory network which suppresses reflex modulation of the respiratory pattern to decrease ventilatory pattern variability. During systemic inflammation, respiratory rate and predictability of the ventilatory pattern increase. These maladaptive changes persist in the absence of peripheral sensory inputs in in situ brainstem preparations derived from rats with either sterile lung injury or systemic infection, indicating alterations in respiratory network activity. Further, respiratory rate increases in healthy rats following IL-1β microinjections in the nTS. Thus, our data indicate that neuro-inflammation of the brainstem respiratory network drives changes in VPV in these disease processes. We test our hypothesis in the following Specific Aims: 1) to determine anatomic and functional maps of the ponto-medullary respiratory circuits in lipopolysaccharide (LPS) treated rats; 2) to determine if the etiology of the inflammatory process affects neuro-inflammation, maladaptation of respiratory network activity and VPV; 3) to assess the causal relationships between neuro-inflammation, respiratory network activity and VPV and whether anti-neuro-inflammatory therapies will attenuate the increases in respiratory frequency and predictability of VPV and restore healthy respiratory network activity. We will apply recent advances in multi-electrode array technology and analysis to map respiratory local field potentials throughout the ponto-medullary respiratory network to investigate where and how peripheral inflammation maladapts central- and sensory-modulated respiratory pattern formation. We will also generate immuno-histochemical maps of the distribution of key early pro-inflammatory cytokines in the brainstem. Electro- physiologic and anatomic atlases will be co-registered to the Waxholm MRI atlas of the rat brain to enable analysis of their relationships. In total, we will use this innovative approach to quantitatively investigate the impact of systemic and neuro-inflammation on the function of an intact neural network. This project is a collaboration between Case Western Reserve University (CWRU, Cleveland, OH) and the Florey Institute (Melbourne, Australia). Frank Jacono (PI, Chief of Pulmonary Critical Care and Sleep Me...