# Noradrenergic mechanisms in breathing and respiratory pathophysiologies

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $583,115

## Abstract

PROJECT SUMMARY ABSTRACT
This renewal focuses on extending the novel findings developed in the current grant to delineate underlying circuit and
molecular mechanisms in noradrenergic (NA) respiratory function and to determine how NA dysfunction may play a role
in two life threatening pathophysiologies, Rett Syndrome and Sudden Infant Death Syndrome (SIDS). Rett Syndrome is
the leading neuro-developmental disorder in females, presents with severe breathing perturbations, and is associated
with NA abnormalities. SIDS is the leading cause of neonate mortality in the United States, claiming 7-14 infants each
day and has been associated with NA abnormalities or other circuits that interact with the central NA system. To gain
additional insight into NA mechanisms in each of these pathophysiologies, we have developed several intersectional and
chemogenetic neural circuit mapping tools that have allowed us to subdivide the NA system into subpopulations defined
by their developmental origin for functional assessment in the adult mouse. With these circuit mapping tools and
technical enhancements from our laboratory in respiratory measurement techniques, we have found that NA neurons
derived from hindbrain rhombomeres 3 and 5 (transient genetically defined segments that embryonically pattern the
hindbrain and resulting brainstem; r3,5) give rise to NA sub-types that when chemogenetically silenced, reduce the
hypercapnic reflex and when chemogenetically stimulated, enhance the hypercapnic reflex. Leveraging these findings
and technical innovations, we have launched three novel areas of research in the NA system. 1) What are the
molecular mechanisms in NA system efferent signaling that are important in the hypercapnic reflex? A
significant number of r3,5 neurons co-express the neurotransmitter glutamate. Additionally, preliminary data indicates
that removing NA production from only r3,5 NA neurons does not affect the hypercapnic reflex, suggesting another
transmitter, such as co-expressed glutamate plays a role or can compensate. 2) What role do rhombomere 3,5 NA
neurons play in Rett disordered breathing. Our preliminary data suggests that chemogenetic stimulation of r3,5 NA
neurons in a mouse Rett model enhances an otherwise nearly absent hypercapnic reflex, indicating that these neurons
are still able to drive or modulate chemosensory function in a disease background. 3) What role does the NA system
play in the protective neonate auto-resuscitation reflex? Failure of the neonate auto-resuscitation reflex is thought to
be a common endpoint for many SIDS cases. We hypothesized that NA chemogenetic stimulation would enhance
neonate (P8) auto-resuscitation after a SIDS like challenge. However, we found that stimulation resulted in a near 50%
increase in mortality while NA system inhibition appears to enhance survival by 50%. In the proposed work, we seek to
determine the molecular and circuit organization of key NA subpopulations in breathing as well as two imp...

## Key facts

- **NIH application ID:** 9973370
- **Project number:** 2R01HL130249-06
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Russell S Ray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,115
- **Award type:** 2
- **Project period:** 2016-01-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973370

## Citation

> US National Institutes of Health, RePORTER application 9973370, Noradrenergic mechanisms in breathing and respiratory pathophysiologies (2R01HL130249-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9973370. Licensed CC0.

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