An important objective in the treatment of the hyperreflexia that follows spinal cord injury is to understand the mechanisms that control plastic alterations in reflex gain. Recently, we have discovered that serotonin (5-HT) can potently and reproducibly facilitate spinal reflexes for hours. These actions resemble persistent flexion reflex responses seen following nociceptive stimuli, and suggest that both primary afferents and descending systems can modulate the gain of the spinal interneurons interposed in flexor reflex afferent (FRA) pathways. """"""""Unfortunately, much less is known about the FRA interneurons than other interneurons"""""""". Hence, we propose to use the easily- inducible augmentation in FRA pathways by 5-HT to undertake a detailed analysis of the network, cellular, and molecular mechanisms controlling plasticity of this well known behavior, the flexor withdrawal reflex. 1 We propose to characterize the afferent and interneuronal populations involved in the 5-HT-induced reflex facilitation to test the hypothesis that the flexor reflex afferent (FRA) interneurons are preferentially facilitated by 5-HT. 2 Injury- inducing noxious stimuli lead to the activation of protein kinase C (PKC) and a long-lasting plasticity in spinal neurons. Because 5-HT2 receptors also activate PKC, we propose to test the hypothesis that 5-HT2 receptors mediate the 5-HT-induced long- lasting facilitation of spinal reflexes via activation of PKC. 3 We then propose to use cellular/molecular approaches to identify `molecular markers' selective to interneurons serving facilitated reflexes. We hypothesize that membrane translocation of the PKCgamma and/or PKCepsilon isozymes will identify the facilitated interneurons. Using similar techniques, we will also test the hypothesis that the hyperreflexia that follows chronic spinal cord injury is due to a novel expression of constitutively active PKC isozymes. In summary, this proposal will use a multidisciplinary approach to characterize a newly-discovered form of plasticity in spinal cord reflex pathways. Information derived from these studies should provide insights into controlling the hyperreflexia that follows spinal cord injury so that the flexion reflex other behaviors that utilize the same spinal circuitry (e.g. locomotion) are allowed to function within a normal range of sensori-motor gain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040893-02
Application #
6394382
Study Section
Special Emphasis Panel (ZNS1-SRB-L (01))
Program Officer
Heetderks, William J
Project Start
2000-09-20
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$332,484
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ziskind-Conhaim, Lea; Hochman, Shawn (2017) Diversity of molecularly defined spinal interneurons engaged in mammalian locomotor pattern generation. J Neurophysiol 118:2956-2974
Hochman, Shawn; Gozal, Elizabeth A; Hayes, Heather B et al. (2012) Enabling techniques for in vitro studies on mammalian spinal locomotor mechanisms. Front Biosci (Landmark Ed) 17:2158-80
Hochman, Shawn (2011) Long-term patch recordings from adult spinal neurons herald new era of opportunity. J Neurophysiol 106:2794-5
Hayes, Heather Brant; Chang, Young-Hui; Hochman, Shawn (2009) An in vitro spinal cord-hindlimb preparation for studying behaviorally relevant rat locomotor function. J Neurophysiol 101:1114-22
Machacek, David W; Hochman, Shawn (2006) Noradrenaline unmasks novel self-reinforcing motor circuits within the mammalian spinal cord. J Neurosci 26:5920-8
Shay, Barbara L; Sawchuk, Michael; Machacek, David W et al. (2005) Serotonin 5-HT2 receptors induce a long-lasting facilitation of spinal reflexes independent of ionotropic receptor activity. J Neurophysiol 94:2867-77
Dougherty, Kimberly J; Sawchuk, Michael A; Hochman, Shawn (2005) Properties of mouse spinal lamina I GABAergic interneurons. J Neurophysiol 94:3221-7
Machacek, D W; Garraway, S M; Shay, B L et al. (2001) Serotonin 5-HT(2) receptor activation induces a long-lasting amplification of spinal reflex actions in the rat. J Physiol 537:201-7