The fundamental hypothesis guiding this proposal is that reduced synaptic inputs to respiratory motor neurons elicits compensatory plasticity, preserving respiratory motor output in a range compatible with life. Our specific goal in the present project period is to investigate cellular mechanisms giving rise to inactivity-induced phrenic motor facilitation (iPMF), a persistent increase in phrenic burst amplitude following prolonged decreases in phrenic neural activity. Two distinct methods of reducing phrenic activity will be studied in anesthetized rats: one that reduces overall activity in the respiratory network (hypocapnia) and another that specifically decreases spinal synaptic inputs to phrenic motor neurons (C2 axon conduction block). The iPMF evoked by these methods exhibits striking similarities, yet may have important differences. Hypocapnia and C2 conduction block both elicit iPMF (i.e., increased amplitude), but only hypocapnia elicits phrenic burst frequency facilitation suggesting the possibility of that iPMF arises from multiple mechanisms depending on whether neural activity was reduced localy versus globally. In this project, we will focus on spinal mechanisms leading to iPMF. Our working model is that reduced synaptic input to phrenic motor neurons stimulates TNF? release in the phrenic motor nucleus (Aim 1), activating atypical PKC (aPKC) isoforms in or near phrenic motor neurons that give rise to iPMF (Aims 2 and 3). We further propose that iPMF is subject to regulatory constraints, similar to other forms of neuroplasticity. By investigations of a unique sub-strain of Sprague Dawley rats, we will gain critical insights concerning mechanisms that constrain iPMF. In specific, we hypothesize that greater constitutive NMDA-glutamateric receptor activity constrains iPMF in this rat sub-strain (Aim 4), possibly due to genetic or epigenetic factors. Since failure to elicit iPMF may contribute to ventilatory control disorders of importance to human health, such as ventilatory weaning failure following prolonged ventilatory support, differences in constitutive NMDA receptor activity may diferentiate patients that successfully wean from ventilatory support versus those that do not. A detailed understanding of cellular cascades giving rise to 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.

Public Health Relevance

Since breathing is necessary for life, failure to restore adequate breathing after prolonged periods of ventilatory support represents a serious clinical problem. In this project we will investigate a highly novel mechanism of spinal cord plasticity induced by periods of reduced breathing effort. Through a detailed understanding of this mechanism, we hope to understand the neural basis of ventilator weaning failure and to develop treatments for patients that have difficulty resuming unassisted breathing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105511-04
Application #
8586344
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$330,633
Indirect Cost
$105,633
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
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
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
Baker-Herman, Tracy L; Strey, Kristi A (2011) Similarities and differences in mechanisms of phrenic and hypoglossal motor facilitation. Respir Physiol Neurobiol 179:48-56