Ongoing collaborations between neuroscientists at the Washington University School of Medicine, Medical College of Ohio, University of Kansas, and Louisiana State University will continue to address mechanisms responsible for normal development and injury-induced reorganization in mammalian sensory systems. The central trigeminal (V) representation of the rodent whiskers (barrels) and limbs will be used to test hypotheses pertaining to: 1) neutrophic regulation of sensory axon growth rate and mode during development; 2) neurotrophin-regulated axon branching and sensory end-organ morphogenesis; 3) mechanism underlying the loss of central V barrel-like patterns after interruption of axonal transport in the developing V nerve; 4) neutrophic control of thalamocortical development; 5) the role of a serotonin receptor and transporter in barrel development and thalamocortical axon outgrowth; and 6) mechanisms subserving cortical expression of sensory information after neonatal limb amputation. An Administrative/Morphology CORE (A) will provide a single neuron labeling facility, electron microscopy, administrative support, and ensure timely communication between projects and external review. A Transgenic Mouse CORE (B) will generate new transgenic models where neurotrophin expression is induced and regulated in selected targets during specified periods in development. An Image Analysis and Morphometry CORE (C) offers a variety of standardized options for quantitative analyses of relevant features in histological preparations. PROJECT 1 will use in vitro organotypic tissue culture and in vivo transgenic over-expression methods to uncover neurotrophin actions during developing V primary afferents and whisker-related pattern formation. PROJECT 2 will assess how the neurotrophin NT3, and the transcription factor, Egr3, regulate the development of limb proprioceptive axons and how these actions modify the function of muscle spindles. PROJECT 3 will reveal the necessary conditions for maintenance of patterns in the V neuraxis; anatomical methods will test the hypothesis that attenuation of axoplasmic transport in the immature V nerve causes a disappearance of central barrel-like patterns secondary to the loss of patterned delivery in neurotrophin from the periphery to the brainstem. PROJECT 4 will use mice with augmented levels of cortical neurotrophins produced by controlled transgenic over-expression in host or transplanted embryonic stem cells, to test the hypothesis that development, and that the spatial and temporal distribution of neurotrophins determines thalamocortical structure and function. PROJECT 4 will employ transgenic mice and pharmacologic methods to test the hypothesis that the 5THT1B receptor and the serotonin transporter mediate the activity-independent effects of serotonin on thalamocortical development. PROJECT 6 uses anatomic, pharmacologic, and electrophysiologic methods to reveal substrates for altered sensory information processing in the S1 cortex after neonatal forelimb removal.
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