# Neuroinflammation Maladapts Cardio Respiratory Circuits and Patterns

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $616,942

## Abstract

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...

## Key facts

- **NIH application ID:** 10840407
- **Project number:** 5R01HL161582-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Frank Joseph Jacono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,942
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840407

## Citation

> US National Institutes of Health, RePORTER application 10840407, Neuroinflammation Maladapts Cardio Respiratory Circuits and Patterns (5R01HL161582-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10840407. Licensed CC0.

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