I Multiple forms of spontaneous respiratory neuroplasticity occur at spinal and brainstem levels in adult rats after lesions to the cervical spinal cord. The goal of this proposal is to enhance naturally occurring processes that can lead to partial improvement of phrenic motoneuron (PhMN) functions that were initially lost or modified after high cervical spinal cord injury (SCI) andto define underlying changes in the neural substrate. Current understanding of neuroplasticity in the phrenic motor system (PhMtrS) derives from studies of spinal hemilesions made above the phrenic nucleus (e.g., at C2). That injury abolishes descending inspiratory drive to ipsilateral PhMNs and renders the corresponding ipsilateral diaphragm (ipsiDIA) hemiparetic. We and others have recently described spontaneously emerging changes in PhMN function after C2 HMx - two of which are emphasized in the proposal. One entails a partial spontaneous recovery of ipsilateral diaphragm activity. The second involves a specific change in contralateral PhMN responses to elevated respiratory drive (hypercapnia).
Aim 1 will test the hypothesis that spontaneous, partial recovery of ipsiPhMN function following a C2 HMx entails neural circuit remodeling via the recruitment of interneurons.
Aim 2 will test the hypothesis that stimulation of axonal growth by blockade of the Nogo- receptor (NgR), using the NgR antagonist, NEP1-40, will enhance spontaneously evolving ipsilateral PhMN functional recovery and possibly amplify the novel circuit to be defined in Aim 1, as well as contribute to modification of contralateral PhMN neuroplastic responses to respiratory challenge.
The third Aim will test the hypothesis that introduction of a novel short propriospinal circuit via neural tissue transplantation can modify, alone or in combination with NEP1-40 delivery, ipsi- and contralateral PhMN neuroplastic responses following C2 HMx injury. We also will assess whether engraftment and therapeutic efficacy of FSC tissue can be complemented by NgR blockade. A multidisciplinary approach will be used involving transneuronal tracing, quantitative neurophysiological indices, and an innovative approach for obtaining repeated measures of breathing in freely-behaving rats.
These aims i dentify with the long-range hypothesis that segmental gray matter repair and neural circuit remodeling provide an effective complement or alternative to long-tract regeneration via enhancement or modification of post-injury neuroplastic events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054025-05
Application #
7744007
Study Section
Special Emphasis Panel (ZRG1-BDCN-B (02))
Program Officer
Kleitman, Naomi
Project Start
2006-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$314,702
Indirect Cost
Name
University of Florida
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Nair, Jayakrishnan; Bezdudnaya, Tatiana; Zholudeva, Lyandysha V et al. (2017) Histological identification of phrenic afferent projections to the spinal cord. Respir Physiol Neurobiol 236:57-68
Lee, Kun-Ze; Sandhu, Milapjit S; Dougherty, Brendan J et al. (2015) Hypoxia triggers short term potentiation of phrenic motoneuron discharge after chronic cervical spinal cord injury. Exp Neurol 263:314-24
Gonzalez-Rothi, Elisa Janine; Rombola, Angela M; Rousseau, Celeste A et al. (2015) Spinal interneurons and forelimb plasticity after incomplete cervical spinal cord injury in adult rats. J Neurotrauma 32:893-907
Gonzalez-Rothi, Elisa J; Lee, Kun-Ze; Dale, Erica A et al. (2015) Intermittent hypoxia and neurorehabilitation. J Appl Physiol (1985) 119:1455-65
Sandhu, M S; Baekey, D M; Maling, N G et al. (2015) Midcervical neuronal discharge patterns during and following hypoxia. J Neurophysiol 113:2091-101
Kwon, Brian K; Soril, Lesley J J; Bacon, Mark et al. (2013) Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough? Exp Neurol 248:30-44
Reier, Paul J; Lane, Michael A; Hall, Edward D et al. (2012) Translational spinal cord injury research: preclinical guidelines and challenges. Handb Clin Neurol 109:411-33
Dougherty, B J; Lee, K Z; Gonzalez-Rothi, E J et al. (2012) Recovery of inspiratory intercostal muscle activity following high cervical hemisection. Respir Physiol Neurobiol 183:186-92
Lane, Michael A; Lee, Kun-Ze; Salazar, Krystal et al. (2012) Respiratory function following bilateral mid-cervical contusion injury in the adult rat. Exp Neurol 235:197-210
Dougherty, Brendan J; Lee, Kun-Ze; Lane, Michael A et al. (2012) Contribution of the spontaneous crossed-phrenic phenomenon to inspiratory tidal volume in spontaneously breathing rats. J Appl Physiol (1985) 112:96-105

Showing the most recent 10 out of 23 publications