# Brainstem Neural Mechanisms Mediating Sympathetic Activation by Chronic Intermittent Hypoxia

> **NIH NIH P01** · UNIVERSITY OF CHICAGO · 2022 · $493,763

## Abstract

Project Summary- Project 2
Sleep apnea (SA) is a major health burden and chronic intermittent hypoxia (CIH) is a hallmark manifestation
of SA. The overall goal of Project 2 aims at determine how CIH acting on key central nervous system (CNS)
structures mediate sympathetic activation through the carotid body (CB). SA patients and CIH exposed rodents
exhibit pronounced sympathetic nerve activation during the post-inspiratory phase of the respiratory cycle.
While the Paraventricular nucleus (PVN) receives sensory input from the CB and is a major regulator of
sympathetic tone. We recently discovered a neural network that mediates post-inspiratory activity in the
brainstem: the post-inspiratory complex (PiCo). We test the hypothesis that PiCo and PVN are the major CNS
areas that are critical for mediating CB reflex-dependent sympathetic excitation by CIH. We test this possibility
using a combination of physiological, electrophysiological, and optogenetic approaches on rats and mice
exposed to CIH, as well as in a mouse of model of sleep apnea, and brainstem slices. AIM 1 determines
whether CIH increases excitability in PiCo. AIM 2 determines whether CIH alters the excitability of
rostroventrolateral medulla sympathetic pre-motoneurons via PiCo. Experiments in AIM 3 addresses the
influence of CIH on the interaction between PVN and PiCo. AIM 4 determines the functional role of PiCo and
PVN in mediating the increased sympathetic drive caused by CIH. AIM 5 examines the role of PiCo and PVN
in mediating increased sympathetic drive and apneas in HO-2 null mice which exhibit spontaneous sleep
apnea. Major conceptual and technical innovations of Project 2 include: a) identification for role of PiCo in
mediating increased sympathetic nerve activity by CIH, b) the delineation of a complete neural circuit
responsible for increased sympathetic nerve activity by CIH, c) use of the state-of-the-art optogenetic
approaches to determine the involvement of different neuronal circuits, and d) examination of central pre-motor
circuits controlling sympathetic tone in a novel mouse model that exhibits spontaneous apneas. Members of
the investigative team have long-standing experience and expertise with the proposed approaches, were the
first to identify PiCo, and have an excellent track record of working together for number years as evidenced by
joint publications. Successful completion of Project 2 is anticipated to establish a framework of understanding
the CNS circuits causing increased sympathetic nerve activation and may lead to novel effective therapies for
mitigating CB reflex- dependent sympathetic activation.

## Key facts

- **NIH application ID:** 10409554
- **Project number:** 5P01HL144454-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Jan M. Ramirez
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $493,763
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409554

## Citation

> US National Institutes of Health, RePORTER application 10409554, Brainstem Neural Mechanisms Mediating Sympathetic Activation by Chronic Intermittent Hypoxia (5P01HL144454-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10409554. Licensed CC0.

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