# Unraveling respiratory rhythm generation in the medullary network

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $662,145

## Abstract

PROJECT SUMMARY
Breathing is vital for survival, and failure to breathe is fatal. This has become tragically evident in the context of
the current opioid crisis. Breathing disturbances are also the cause of sleep apnea, which is another health
issue of epidemic proportions. At the core of all these disturbances are neuronal networks located within the
brainstem. Two of these networks, the preBötzinger complex (preBötC) and the parafacial respiratory group
(pFRG) are thought to give rise to inspiration and active expiration, respectively. During the initial funding
period of this grant, we identified a third excitatory microcircuit, the postinspiratory complex (PiCo), which gives
rise to a third breathing phase: postinspiration – the expiratory phase that follows inspiration. Based on our
discovery, we proposed the triple oscillator hypothesis: i.e. three excitatory microcircuits (preBötC, pFRG,
PiCo) give rise to the three phases of breathing. However, the discovery of PiCo raised an important,
unresolved issue: what is the role of the so-called Bötzinger complex (BötC), a fourth region that contains
respiratory neurons, and that is located rostral of the preBötC?
Here we test the overarching hypothesis that the preBötC is not a small microcircuit, as previously thought, but
that this network forms a dynamically regulated column contiguous with the BötC. The extent of this column is
dynamically regulated by synaptic inhibition, chemo- and mechanosensory afferents. The project tests this
hypothesis in three specific aims: Aim 1 maps the extent of respiratory activity along the medullary column. We
will use electrophysiological, calcium imaging and optogenetic approaches to characterize the neuronal
discharge patterns within this column. Aim 2 investigates the cellular determinants that control the extent of this
column using intracellular and optogenetic recordings. We specifically test the hypothesis that a balance
between synaptic inhibition, and excitation regulates the regularity, frequency and spatial extent of the column.
To conduct aims 1 and 2 we will employ horizontal brainstem slices that isolate the entire ventral medulla and
that are amenable to a rigorous cellular and network analysis. Aim 3 explores the dynamic regulation of the
column in alert and anesthetized in vivo animals. We test the hypothesis that vagal and chemosensory
afferents play a critical role in regulating the spatial extent of this column by activating inhibitory neurons that
are capable of shrinking and extending the inspiratory rhythmogenic network. The proposed research may lead
to a better understanding of the fundamental question: how the brain generates rhythmic motor activity and
how it integrates sensory information. Insights gained will also have important implications for understanding
the cellular and systems level mechanisms underlying the mortality and morbidity associated with breathing
disorders.

## Key facts

- **NIH application ID:** 10447726
- **Project number:** 5R01HL126523-08
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Jan M. Ramirez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $662,145
- **Award type:** 5
- **Project period:** 2015-01-01 → 2024-04-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447726

## Citation

> US National Institutes of Health, RePORTER application 10447726, Unraveling respiratory rhythm generation in the medullary network (5R01HL126523-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447726. Licensed CC0.

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