Neuroinflammation disrupts cardio-respiratory circuits and patterns

Inflammation of the central nervous system (CNS) develops in both sepsis (systemic infection) as well as sterile lung injury. The neuro-inflammation mirrors the peripheral inflammation and affects the neural control of respiration. We have published that neuro-inflammation in the nuclei tractus solitarii (nTS, dorsomedial medulla)

decreases synaptic efficacy of vagal sensory feedback and increases the predictability of ventilatory pattern variability (VPV). Further, healthy rats increase their respiratory rate (fR) and ventilatory pattern predictability following IL-1β microinjections in the nTS. Thus, while we have an understanding that peripheral inflammation is

reflected in the nTS and affects breathing at molecular and functional levels, the effects at the level of the complete respiratory network remain obscure. Our hypothesis is that brainstem neuro-inflammation alters respiratory network function including diminishing regulatory sensory feedback that ultimately

decreases VPV. The increases in fR and predictability of the ventilatory pattern persist in in situ brainstem preparations that are derived from rats with lung injury or with peritonitis. This indicates alterations in respiratory network function are mediated via alterations in the central control of breathing. Thus, published and preliminary

data indicate that neuro-inflammation of the brainstem drives changes in ventilation. We test our hypothesis in the following Specific Aims: 1) to correlate neuro-inflammation, respiratory network function (assessed by VPV) and create an anatomic and functional atlas of the ponto-medullary respiratory

circuits in sham and lipopolysaccharide-treated rats, 2) to determine if etiology of the inflammatory process affects patterns of neuro-inflammation and disruptions of respiratory network function, and 3) to determine if therapies that reduce neuro-inflammation attenuate increases in fR and predictability of VPV, and consequently

restore network function. We will apply recent advances in multi-electrode array technology and analysis to record respiratory- modulated ensemble single-unit activities across nuclei of the ponto-medullary respiratory network. In Aim 1, we will answer where and how neuro-inflammation disrupts central- and sensory-modulated respiratory network

activity and connectivity associated with changes in VPV. Electrophysiologic and anatomic datasets will be co- registered to the Waxholm MRI atlas of the rat brain to enable analysis of their relationships. In Aim 2, we will determine if the etiology of inflammation is reflected in neuro-inflammation and respiratory dysfunction. In Aim 3,

we will determine if targeting neuro-inflammation in peritonitis restores respiratory network function and VPV. In summary, we will use this innovative approach to investigate the impact of neuro-inflammation on the function of an intact neural network. These studies will support the clinical translation of VPV as an early biometric of

disease progression and identify neuro-inflammation as a novel therapeutic target. The experimental team consisting of Frank Jacono (PI; Louis Stokes Cleveland VAMC and Chief of Pulmonary Critical Care and Sleep Medicine at CWRU), Rishi R. Dhingra, Thomas E. Dick and Yee-Hsee Hsieh (co-Investigators; CWRU) has the expertise to conduct these studies.