Restless legs syndrome (RLS) is a CNS disorder involving abnormal muscle sensations that are reduced during motor activity, worsen at rest, and have a marked circadian pattern. Primary treatment involves providing drugs that increase CNS dopaminergic activity, particularly activation of D2-1ike receptors. The hypothalamus controls autonomic function and circadian rhythmicity. The dorso-posterior (A11) region contains the only dopaminergic (DA) projections to spinal cord. DA fibers terminate largely in the intermediolateral column (IML) housing preganglionic sympathetic neurons and in dorsal horn regions related to muscle afferent processing. We hypothesize: (i) That a deficit in hypothalamo-spinal DA activity results in an aberrant activation of muscle afferents; directly, by reducing tonic inhibition of afferent input, and; indirectly, via a disinhibition-induced increase in sympathetic drive to skeletal muscle afferents. (ii) That low-threshold afferent activity (e.g. during movement) presynaptically depresses high-threshold muscle afferents. (iii) That DA disinhibitory actions should peak at night, the nadir of hypothalamic circadian dopamine release. As the A11 region provides the only DA input, all spinal modulatory actions can be ascribed to its function. Hence, studies of DA modulatory actions in the in vitro spinal cord will characterize the complex cellular and network actions of hypothalamo-spinal dopamine function. First, we plan to characterize the dopamine receptor distribution in spinal cord using immunostaining and in situ hybridization techniques. We will then study 5-HT and dopamine modulation of IML neuronal excitability and whether increases in sympathetic drive facilitate muscle afferent activity and input to spinal neurons. Lastly, we will use A11 neurochemical lesioning and D3 receptor knockout mice to examine their effects on alterations in spinal cord function and relate these changes to changes in several movement-related behavioral parameters concomitant with recordings of EEG, neck & limb EMG, and EKG. The uniqueness of our proposal is the development of novel and testable hypotheses on putative spinal mechanisms causing RLS. It involves the first detailed study of DA modulation of spinal cord function and it is undertaken at behavioral, network, and cellular levels, including an attempt to develop an animal model of RLS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-2 (01))
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Mitler, Merrill
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Emory University
Schools of Medicine
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Hochman, Shawn; Hayes, Heather Brant; Speigel, Iris et al. (2013) Force-sensitive afferents recruited during stance encode sensory depression in the contralateral swinging limb during locomotion. Ann N Y Acad Sci 1279:103-13
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
Hayes, Heather Brant; Chang, Young-Hui; Hochman, Shawn (2012) Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion. J Neurophysiol 107:3168-80
Hochman, Shawn (2011) Long-term patch recordings from adult spinal neurons herald new era of opportunity. J Neurophysiol 106:2794-5
Zimmerman, Amanda; Hochman, Shawn (2010) Heterogeneity of membrane properties in sympathetic preganglionic neurons of neonatal mice: evidence of four subpopulations in the intermediolateral nucleus. J Neurophysiol 103:490-8
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
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Dougherty, Kimberly J; Hochman, Shawn (2008) Spinal cord injury causes plasticity in a subpopulation of lamina I GABAergic interneurons. J Neurophysiol 100:212-23
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Zhu, H; Clemens, S; Sawchuk, M et al. (2007) Expression and distribution of all dopamine receptor subtypes (D(1)-D(5)) in the mouse lumbar spinal cord: a real-time polymerase chain reaction and non-autoradiographic in situ hybridization study. Neuroscience 149:885-97

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