The correct operation of the nervous system depends on the formation of highly specific patterns of axonal projections and synaptic connections among nerve cells. To understand how this occurs, the approach taken in this proposal is to study the development of one well characterized set of synaptic pathways in the spinal cord, those involved in the reflex control of muscle length and tension. Sensory neurons supplying muscle spindles (Ia afferents) are primarily sensitive to muscle length; they project into the spinal cord where they make monosynaptic connections with particular subsets of motoneurons. Other proprioceptive sensory neurons (Ib afferents), supplying Golgi tendon organs that are sensitive to active muscle tension, also make specific connections with motoneurons, but these connections are mediated polysynaptically. These issues will be addressed using the isolated neonatal mouse spinal cord preparation. A major advantage of this preparation is that different classes of proprioceptive afferents (Ia and Ib neurons) can be stimulated selectively and intracellular recordings can be made from functionally identified motoneurons. The availability of transgenic and knock-out mice makes it possible to test the role of specific molecules and cell types in generating these specific patterns of connections. The experiments proposed here examine how each of these pathways develops. For the Ia pathway from muscle spindles, we will focus on the role played by the spindle itself in providing trophic support and instructive guidance for Ia sensory neurons, both during embryonic development and during the neonatal period when synaptic connections are still being formed. We will also test if the ETS gene family of transcription factors is involved in helping to specify the pattern of Ia sensory-motor synapses. For the polysynaptic Ib pathway, we will determine if the projections develop specifically from the outset, as for Ia connections, or if synaptic patterns are remodeled as in other parts of the nervous system. Although the experiments in this proposal are confined to normal development, it is likely that knowledge of the mechanisms involved in the formation of spinal pathways during development will be useful in developing strategies for the reconstruction of these pathways after spinal injury.
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