# Mechanisms and significance of inactivity-induced respiratory plasticity

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $382,500

## Abstract

PROJECT SUMMARY/ABSTRACT
In the first funding period, we discovered that local mechanisms sense and respond to a
reduction in synaptic inputs to phrenic motor neurons to elicit compensatory enhancement of
phrenic motor output, a novel form of plasticity that we termed inactivity-induced phrenic motor
facilitation (iPMF). We defined key cellular pathways that give rise to iPMF following prolonged
reductions in phrenic neural activity and found that these same mechanisms do not give rise to
iPMF following intermittent reductions in phrenic neural activity. Since many clinical disorders
are characterized by recurrent, brief reductions in respiratory neural activity, our specific goal in
the present project period is to investigate cellular mechanisms that give rise to iPMF following
intermittent phrenic neural hypoactivity and begin studies investigating the role for iPMF in the
control of breathing. Our working model is that intermittent reductions in phrenic synaptic inputs
stimulates retinoic acid synthesis in the phrenic motor nucleus, which activates RARα receptors
in phrenic motor neurons to increase activity of the atypical PKC isoform PKCζ and give rise to
iPMF (Aim 1). We hypothesize that spinal mechanisms that give rise to iPMF result in a lowering
of the CO2 threshold for phrenic inspiratory activity (Aim 2). We propose that induction of a
distinct form of plasticity known as phrenic long-term facilitation (pLTF) by concurrent exposure
to hypoxia undermines iPMF due to an NMDA receptor-mediated constraint of the cellular
pathways giving rise to iPMF (Aim 3). Our fundamental hypothesis is that iPMF is a
compensatory mechanism that detects and corrects reductions in phrenic motor output, thereby
preventing apneas and hypopneas (Aim 4). A detailed understanding of cellular cascades giving
rise to and constraining iPMF is essential to understand the physiological role of this highly
novel form of plasticity, and—importantly—to identify promising therapeutic targets for
pharmacological interventions to treat respiratory control disorders characterized by recurrent
disruptions in respiratory neural activity, such as central sleep apnea.

## Key facts

- **NIH application ID:** 9843694
- **Project number:** 5R01HL105511-09
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Tracy L Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2011-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843694

## Citation

> US National Institutes of Health, RePORTER application 9843694, Mechanisms and significance of inactivity-induced respiratory plasticity (5R01HL105511-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9843694. Licensed CC0.

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