Peripheral nerve degeneration following injury has implications not only for the denervated target, but also for intact heterologous nerves. For example, sympathetic denervation causes changes in both structure and molecular phenotype of intact sensory and parasympathetic nerves projecting to a common target. Our preliminary studies show that heterologous nerve function can also be affected. Parasympathetic nerves innervating the rat superior tarsal muscle, an orbital smooth muscle, normally attenuate muscle contraction by inhibiting neurotransmission of excitatory sympathetic nerves. However, by 5 weeks after sympathectomy, parasympathetic nerves have become excitatory, eliciting a muscarinic cholinergic contraction; this is not attributable to muscle supersensitivity or diminished enzymatic degradation of acetylcholine, and is therefore believed to be due to changes occurring at the level of the nerve. Our objective is to determine mechanisms responsible for functional conversion, and its relevance to ameliorating deficits after nerve injury. The applicant hypothesizes that, as a result of sympathectomy, excitatory parasympathetic neuromuscular transmission is established because of increased neuroeffector contacts and/or increased transmitter production and release. The applicant further postulates that this occurs because of altered neurotrophic factor levels within the target, that it attenuates denervation- induced target deficits, and that it occurs in systems other than orbital smooth muscle.
The specific aims are to further characterize parasympathetic functional conversion after sympathectomy by determining: (1) its time course, (2) if it is associated with more intimate neuromuscular contacts, (3) if changes occur in numbers of parasympathetic fibers, and (4) whether it is accompanied by increased activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase. In addition, the applicant will determine (5) if it can be modulated by changing the availability of target-derived neurotrophic molecules, (6) if smooth muscle atrophy and supersensitivity are ameliorated, and (7) if functional conversion can be demonstrated in blood vessels of the eye and orbit. These studies investigate a novel and potentially important form of neuroplasticity. An understanding of this phenomenon will provide not only a clearer picture of its mechanism and prevalence, but also may give insight into how it can be manipulated to reverse denervation- induced target deficits, thus leading to improved medical rehabilitation strategies after nerve injury.
