As the nervous system develops, neurons become specified to make precise patterns of synaptic connections. Some aspects of neuronal phenotype are likely to be determined by a cell's lineage and its position within the developing embryo. Chemical signals present in a neuron's target tissue provide another mechanisms for influencing a cell's developmental fate. Neural activity can also shape the final pattern of synaptic connections. A knowledge of how these three mechanisms operate is basic to an understanding of how nerve cells originally make and then refine and maintain operate is basic to an understanding of how nerve cells originally make and then refine and maintain their proper connections. Synaptic connections in the spinal cord made by primary sensory afferent fibers innervating muscle and skin provide an excellent system for studying this problem at the level of single, functionally identified cells. Sensory neurons innervating muscle spindles form monosynaptic connections with spinal motoneurons, whereas cutaneous sensory neurons do not. The peripheral targets of sensory neurons are important determinants of the relative numbers of muscle vs. cutaneous cell types. A major aim of this proposal is to determine if this effect is caused by the selective survival of pre-determined sensory neurons, or if peripheral targets have an instructive effect on sensory neuron phenotype. Sensory fibers in the frog can regenerate after they are interrupted in the dorsal root. Although they re-innervate motoneurons with a high degree of specificity, they do not re- establish their long-fiber tracts within the dorsal columns.
A second aim of this proposal is to see if neurite-promoting factors that work in vitro will also stimulate axon regeneration within the white matter of the spinal cord. Such studies may help in achieving regeneration in human spinal cord after accidental injury. Finally, we propose to continue our studies of the mechanism of presynaptic inhibition of sensory-motor synapses in the amphibian spinal cord. Synaptic transmission between muscle spindle afferents and motoneurons, the pathways that mediates the simple stretch reflex, is inhibited by stimulation of other sensory afferents. Previous work has shown that a major portion of this inhibition is presynaptic and is mediated by the neural transmitter GABA. However, activation of both GABAA and GABAB receptors inhibits synaptic transmission in this pathway. Experiments using pharmacological agents to block each of these receptor types should enable us to determine which type is responsible for the inhibition observed physiologically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024373-07
Application #
3408892
Study Section
Neurology C Study Section (NEUC)
Project Start
1986-04-01
Project End
1996-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Zhi; Li, LingYing; Frank, Eric (2012) The role of muscle spindles in the development of the monosynaptic stretch reflex. J Neurophysiol 108:83-90
Wang, Zhi; Li, LingYing; Goulding, Martyn et al. (2008) Early postnatal development of reciprocal Ia inhibition in the murine spinal cord. J Neurophysiol 100:185-96
Hardy, W Rod; Li, Lingying; Wang, Zhi et al. (2007) Combinatorial ShcA docking interactions support diversity in tissue morphogenesis. Science 317:251-6
Wang, Zhi; Li, Ling Ying; Taylor, Michael D et al. (2007) Prenatal exposure to elevated NT3 disrupts synaptic selectivity in the spinal cord. J Neurosci 27:3686-94
Li, L Y; Wang, Z; Sedy, J et al. (2006) Neurotrophin-3 ameliorates sensory-motor deficits in Er81-deficient mice. Dev Dyn 235:3039-50
Oakley, R A; Lefcort, F B; Plouffe, P et al. (2000) Neurotrophin-3 promotes the survival of a limited subpopulation of cutaneous sensory neurons. Dev Biol 224:415-27
Chen, H H; Frank, E (1999) Development and specification of muscle sensory neurons. Curr Opin Neurobiol 9:405-9
Sharma, K; Frank, E (1998) Sensory axons are guided by local cues in the developing dorsal spinal cord. Development 125:635-43
Oakley, R A; Lefcort, F B; Clary, D O et al. (1997) Neurotrophin-3 promotes the differentiation of muscle spindle afferents in the absence of peripheral targets. J Neurosci 17:4262-74
Mears, S C; Frank, E (1997) Formation of specific monosynaptic connections between muscle spindle afferents and motoneurons in the mouse. J Neurosci 17:3128-35

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