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Sympathetic axons invade the trigeminal ganglia of mice overexpressing nerve growth factor (NGF) (NGF/p75(+/+) mice) and surround sensory neurons having intense NGF immunolabeling; the growth of these axons appears to be directional and specific (). In this investigation, we provide new insight into the neurochemical features and receptor requirements of this sympathosensory sprouting. Using double-antigen immunohistochemistry, we demonstrate that virtually all (98%) trigeminal neurons that exhibit a sympathetic plexus are trk tyrosine kinase receptor (trkA)-positive. In addition, the majority (86%) of those neurons enveloped by sympathetic fibers is also calcitonin gene-related peptide (CGRP)-positive; a smaller number of plexuses (14%) surrounded other somata lacking this neuropeptide. Our results show that sympathosensory interactions form primarily between noradrenergic sympathetic efferents and the trkA/CGRP-expressing sensory somata. To assess the contribution of the p75 neurotrophin receptor (p75(NTR)) in sympathosensory sprouting, a hybrid strain of mice was used that overexpresses NGF but lacks p75(NTR) expression (NGF/p75(-/-) mice). The trigeminal ganglia of NGF/p75(-/-) mice, like those of NGF/p75(+/+) mice, have increased levels of NGF protein and display a concomitant ingrowth of sympathetic axons. In contrast to the precise pattern of sprouting seen in the ganglia of NGF/p75(+/+) mice, sympathetic axons course randomly throughout the ganglionic neuropil of NGF/p75(-/-) mice, forming few perineuronal plexuses. Our results indicate that p75(NTR) is not required to initiate or sustain the growth of sympathetic axons into the NGF-rich trigeminal ganglia but rather plays a role in regulating the directional patterns of axon growth.

Previous work suggested that in mouse, presumptive targets of the trigeminal ganglion, rather than intermediate structures, attract pioneer axons from the time their growth cones exit the ganglion (Lumsden and Davies, 1986). In rat we find that some presumptive targets repel trigeminal axons. The repellant activity is concentrated in the anterior and ventral epithelium of the mandibular arch at embryonic day 12 (E12) and was also present in the maxillary arch. The activity is blocked by anti-neuropilin-1. E13 mandible explants repel trigeminal axons during the first day of outgrowth in vitro, but thereafter permit or attract trigeminal ganglion axon outgrowth. By E14, lingual nerve afferents first enter the tongue in vivo, and the repellant influence becomes restricted to the midline. The progressive restriction of the repellant influence may contribute to the in vivo progression of nerve development: the earliest afferents turn anteriorly lateral to the tongue, but subsequently arriving afferents advance into the tongue and then turn away from the midline. Thus, the repellant may influence the order of nerve branch development and the timing of innervation of epithelial and subepithelial targets. Heterochronic studies revealed that the loss of repellant influence from presumptive lateral tongue surface results from downregulation of the repellant activity, not of responsiveness to the repellant. Because presumptive targets repel trigeminal axons during the initial stages of advance from the trigeminal ganglion and do not have a net attractive influence until after afferents have arrived near the target, intermediate structures must guide these axons initially.

In the adult rodent trigeminal ganglion there is a period of postnatal cell death in the population of cells with axons innervating the middle cerebral artery (O'Connor and van der Kooy, 1986b). The superior cervical ganglion (SCG) also has a projection to the middle cerebral artery (MCA; Mayberg et al., 1984; Cowen et al., 1986, 1987; present report). We hypothesized that the trigeminal ganglion cells innervating the MCA may be competing with the superior cervical projection for target area or for a target factor for survival, and thus the removal of the superior cervical projection at birth (sympathectomy) may promote the survival of some of the trigeminal-artery innervating cells that normally would die. Multiple fluorescent retrograde tracing was employed to analyze the postnatal development of the trigeminal projection to the MCA in sympathectomized and sibling control rats. We found that the SCG projection to the MCA exhibits a period of postnatal cell death. The trigeminal ganglion projection exhibits axon degeneration as well as postnatal cell death. Postnatal day 0 (P0) lesioning of the SCG did not prevent cell death or axon loss in the trigeminal projection to the cerebral artery. In fact, increased cell death of the trigeminal-artery projecting neurons was observed in the lesioned animals when compared to nonlesioned sibling controls. By P55, we found that 80% of these trigeminal neurons had died in lesioned animals, compared with 50% in controls. In both control and sympathectomized rats, close to 90% of the trigeminal neurons innervating the artery in the neonate can no longer be retrogradely labeled from the MCA by tracer applications at P25-90. Thus, although the presence of an intact SCG may protect some trigeminal-artery projecting neurons from cell death, it does not prevent axon retraction and does not permit a larger absolute number of trigeminal axons to innervate the arteries in the adult. Thus, separate mechanisms are responsible for the survival of perikarya versus the retraction of their axons from the MCA. Surprisingly, in the neonatally sympathectomized rats almost 20% of those trigeminal cells that maintained a projection to the MCA at P90 also had a projection to the forehead. In contrast, less than 3% of the artery innervating trigeminal cells in the P90 control rats had an axon collateral to the forehead.(ABSTRACT TRUNCATED AT 400 WORDS)