# Neuroglial interactions underlying the generation of the sigh

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $804,333

## Abstract

PROJECT SUMMARY
Sighs are critical for survival. They maintain normal lung functions by preventing atelectasis. Moreover, sighs
have also been implicated in arousal, and failure to sigh has been associated with Sudden Infant Death
Syndrome. The Ramirez lab has demonstrated that sighs are generated within the preBötzinger complex in the
ventrolateral medulla. Indeed, the same neurons that generate eupneic inspiratory rhythmic activity seem to
generate also sighs. This leads to an important, yet unresolved puzzle: How can the same neuronal network
generate two types of breathing rhythm with strikingly different timing characteristics? The eupneic inspiratory
rhythm occurs at a frequency of 1-2 Hz, while sighs are generated in the range of several minutes. Here we
test the hypothesis that sighs are generated by neuroglial interactions that involve purinergic and glutamatergic
interactions between glia and neurons with specific intrinsic and synaptic properties. This hypothesis is tested
in three specific aims: Aim 1 will characterize the glial properties critical for the generation of sighs. We will
evaluate the pharmacological, and neuromodulatory properties of isolated glia, and glia embedded within the
respiratory network, using calcium imaging and optogenetic tools. Aim 2 will characterize the specific neuronal
properties that are critical for the generation of sighs. We will test the hypothesis that these neuronal properties
involve P/Q-type calcium channel dependent synaptic transmission that is modulated by metabotropic
glutamate receptors (mGluR8), as well as intrinsic membrane properties that involve the persistent sodium
current that is modulated by muscarinic receptors and beta-adrenergic receptors. Aims 1 and 2 will be
performed in in vitro slice preparations that are amenable to a rigorous cellular level analysis. These two aims
are complemented by aim 3 in which we will implement our insights gained in vitro in an in vivo preparation that
is also amenable to optogenetic manipulations. This grant will provide critical insights into the generation of the
sigh. In addition, this project will provide fundamental insights into neuroglial interactions. These insights will
not only be relevant in the context of sigh rhythmogenesis, but these studies will also be important for
understanding the generation of rhythmic behaviors in general.

## Key facts

- **NIH application ID:** 10149393
- **Project number:** 5R01HL151389-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Jan M. Ramirez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $804,333
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149393

## Citation

> US National Institutes of Health, RePORTER application 10149393, Neuroglial interactions underlying the generation of the sigh (5R01HL151389-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10149393. Licensed CC0.

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