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 RAR? receptors in phrenic motor neurons to increase activity of the atypical PKC isoform PKC? 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.

Public Health Relevance

Periodic cessations in breathing, such as that which occurs in people with central sleep apnea, represent a serious clinical problem. In this project we will investigate a highly novel mechanism of spinal cord plasticity induced by intermittent periods of reduced breathing effort. Through a detailed understanding of this mechanism, we hope to understand the neural basis of inadequate breathing and to develop treatments for patients with central sleep apnea for which these endogenous mechanisms of plasticity are insufficient.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105511-07
Application #
9402108
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2011-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Braegelmann, K M; Streeter, K A; Fields, D P et al. (2017) Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control? Exp Neurol 287:225-234
Baertsch, N A; Baker, T L (2017) Reduced respiratory neural activity elicits a long-lasting decrease in the CO2 threshold for apnea in anesthetized rats. Exp Neurol 287:235-242
Johnson, Stephen M; Randhawa, Karanbir S; Epstein, Jenna J et al. (2017) Gestational intermittent hypoxia increases susceptibility to neuroinflammation and alters respiratory motor control in neonatal rats. Respir Physiol Neurobiol :
Baertsch, Nathan A; Baker, Tracy L (2017) Intermittent apnea elicits inactivity-induced phrenic motor facilitation via a retinoic acid- and protein synthesis-dependent pathway. J Neurophysiol 118:2702-2710
Baertsch, Nathan A; Baker-Herman, Tracy L (2015) Intermittent reductions in respiratory neural activity elicit spinal TNF-?-independent, atypical PKC-dependent inactivity-induced phrenic motor facilitation. Am J Physiol Regul Integr Comp Physiol 308:R700-7
Streeter, K A; Baker-Herman, T L (2014) Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation. Exp Neurol 256:46-56
Streeter, K A; Baker-Herman, T L (2014) Spinal NMDA receptor activation constrains inactivity-induced phrenic motor facilitation in Charles River Sprague-Dawley rats. J Appl Physiol (1985) 117:682-93
Broytman, Oleg; Baertsch, Nathan A; Baker-Herman, Tracy L (2013) Spinal TNF is necessary for inactivity-induced phrenic motor facilitation. J Physiol 591:5585-98
Baertsch, N A; Baker-Herman, T L (2013) Inactivity-induced phrenic and hypoglossal motor facilitation are differentially expressed following intermittent vs. sustained neural apnea. J Appl Physiol (1985) 114:1388-95
Strey, K A; Baertsch, N A; Baker-Herman, T L (2013) Inactivity-induced respiratory plasticity: protecting the drive to breathe in disorders that reduce respiratory neural activity. Respir Physiol Neurobiol 189:384-94

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