# Unraveling respiratory rhythm generation in medullary and supramedullary networks

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2024 · $953,628

## Abstract

Project Summary
The integration of brain, breathing and the heart is vital to meet the continuously changing metabolic and
behavioral demands of an organism. Consequently, disorders of breathing are rarely limited to breathing
disturbances and typically also include disturbances in cardiorespiratory coupling and arousal. Failure to arouse
can lead to SIDS, while the ability to gasp and arouse is a reliable predictor for a positive long-term outcome
after cardiac arrest. On the other hand, frequent arousals in obstructive sleep apnea result in sleep disturbances.
However, understanding, how the neuronal control of breathing is integrated within the wider nervous system to
control arousal and autonomic motor outputs has been challenging since this requires a broader understanding
of respiratory rhythmogenesis, cardiorespiratory coupling and the ascending and descending control of the
arousal network. This grant will use cutting-edge molecular, genomic and systems level approaches to obtain a
detailed understanding of the connectomes that integrate the respiratory network with the arousal network. The
recently developed Neuropixel approach enabled us to record from thousands of neurons across the CNS which
includes the ventral respiratory column (VRC). Recordings obtained in urethane anesthetized freely breathing
mice reveal that the activity of expiratory and inspiratory neurons along the entire VRC gives rise to rotational
population dynamics which gradually transitions from expiration into inspiration before the respiratory cycle
terminates in the inspiration off-switch. Since expiratory activity is largely absent in isolated in vitro preparations,
Aim 1 will test the hypothesis that the generation of expiratory activity in vivo requires afferent input from the
lungs. We will explore how mechanosensory input controls eupneic breathing by combining lung inflations with
optogenetic stimulations of neurons located in the VRC and nucleus tractus solitarius (NTS). Aim 2 will explore
the reconfiguration of the respiratory network as it transitions from eupnea into gasping. Due to a loss of
expiratory activity, the respiratory network dynamically extends rostrally to generate inspiratory-phased VRC
population activity. We hypothesize that this spatial extension recruits the arousal network. Aim 3 studies the
gasping-induced activation of the arousal network and the effects of vagal stimulations in alert and behaving
animals to test the hypothesis that the arousal network is reciprocally connected with a network that decreases
anxiety. Neuropixel recordings from the medial prefrontal cortex (mPFC), the Locus coeruleus (LC), parabrachial
complex (PB) and basal forebrain (BF) will be combined with targeted opto- and chemogenetic approaches to
gain first insights into the emotional control of breathing.

## Key facts

- **NIH application ID:** 10797384
- **Project number:** 2R01HL126523-09
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Jan M. Ramirez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $953,628
- **Award type:** 2
- **Project period:** 2015-01-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797384

## Citation

> US National Institutes of Health, RePORTER application 10797384, Unraveling respiratory rhythm generation in medullary and supramedullary networks (2R01HL126523-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10797384. Licensed CC0.

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