The long-term objective of this program is an understanding, at the cellular level, of mechanisms involved in recovery from neural injury. This proposal is directed to the role of target innervation in recovery of spinal functions of injured peripheral nerves: specifically, of axotomized motor and sensory neurons of the cat's hindlimb. The general hypothesis to be tested is that innervation of an appropriate target enables recovery of spinal functions of axotomized motor and sensory nerves. Following nerve injury, regenerating sensory fibers may innervate foreign receptors (e.g., a muscle spindle afferent may innervate a tendon organ). Among possible central (i.e., spinal cord) consequences of such foreign innervation are (i) persistence of the afferent's original (now inappropriate) synaptic connections and actions, (ii) modification of central synaptic actions to bring accord with peripheral innervation, and (iii) decline of central synaptic actions. Muscle and cutaneous nerves will be cross- connected, giving regenerating muscle and cutaneous afferents foreign receptors as targets for reinnervation. In electrophysiological experiments, the central synaptic actions of these cross-connected afferents will be tested and compared with those of unoperated afferents, and of afferents which have (i) been cut and ligated or (ii) reinnervated their native or (iii) similar tissue. Two specific hypotheses concerning target requirements will be tested: (i) that afferents do not require receptor innervation to maintain their normal spinal function, and (ii) that receptor innervation is required, but there is latitude in the specific requirements (e.g., foreign receptors may suffice). Similarly, regenerating motor axons may innervate foreign muscle. When medial gastrocnemius motoneurons regenerate into soleus muscle, many of the MG motoneurons fail to recover their normal electrical properties, and they appear as though still axotomized. Cross-innervation, nerve-block and kinesiological experiments will test the specific hypotheses that (i) muscle-derived factors acquired during activity of the neuromuscular synapse permit motoneurons to recover from axotomy, and (ii) motoneurons which fail to recover normal electrical properties following muscle reinnervation fail also to recover normal functional properties. These experiments will provide direct, useful information concerning mechanisms and consequences of neural injury, and on regeneration and recovery of function.
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