Plasticity of mature sensory cerebrovascular axons following intracranial infusion of nerve growth factor

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Abstract
Mature perivascular sympathetic axons associated with the intradural segment of the internal carotid artery (ICA) of the adult rat respond by sprouting following a two week infusion of nerve growth factor (NGF) into the lateral ventricle of the brain. Because nonsympathetic axons such as those comprising the sensory and parasympathetic population have been shown to respond to NGF, the present study was carried out to determine whether mature sensory axons respond to in vivo NGF infusion and whether competitive interactions between the innervating populations might affect the responsiveness of these axons to NGF. Standard electron microscopic techniques as well as calcitonin-gene-related peptide (CGRP) immunohistochemistry at the light microscopic level were used to examine the effects of intracerebroventricular NGF infusion on mature perivascular fibers with and without prior sympathetic denervation (i. e., bilateral superior cervical ganglionectomy). Following NGF infusion, CGRPimmunoreactive fibers appeared thicker and more numerous in the longitudinal plane when compared with vehicle controls. However, at the ultrastructural level, a significant increase in the total number of axons was not observed, although there was an increase in the number of large granular vesicles, suggesting that the CGRP fibers responded to exogenous NGF with an increase in neurotransmitter content, but not by sprouting. Sympathetic denervation, on the other hand, resulted in a significant increase in the number of fibers passing in the circumferential plane. The most dramatic change in CGRP immunoreactivity was observed following combined sympathetic denervation and subsequent NGF infusion, where, in addition to the presence of thicker immunoreactive fibers, a significant increase in the perivascular density of immunoreactive fibers associated with the intradural blood vessels was observed. These findings suggest that exogenous NGF has different effects on mature sympathetic and nonsympathetic fibers that innervate intradural blood vessels. The former exhibit robust sprouting, whereas the latter do not sprout in response to NGF but show evidence for increased neuropeptide content. In addition, the heightened response by sensory axons following denervation and subsequent NGF infusion provides support for the idea that sensory and sympathetic axons normally compete for target space and/or target-derived neurotrophic factors.