Transgenic mice that overexpress nerve growth factor (NGF) in cells producing glial fibrillary acidic protein were used to determine whether sympathetic axons will invade the undamaged, postnatal mammalian brain. By using reverse transcriptase-polymerase chain reaction, NGF mRNA transgene expression was detectable in the hippocampi and cerebella of transgenic mice but not in age-matched, wild type mice. Elevated levels of NGF protein were detected in the hippocampi and cerebella of postnatal and adult transgenic animals as well as in conditioned media from transgenic cerebellar astrocytes in culture. The brains of these transgenic mice were found to contain postganglionic sympathetic fibers, as identified by their immunohistochemical staining for tyrosine hydroxylase and by their disappearance following superior cervical ganglionectomy. In the cerebellum, a robust plexus of sympathetic fibers was evident in the deep white matter and in the inferior cerebellar peduncles. These axons within the cerebellum were observed as early as 14 days after birth and dramatically increased in number with age. Sympathetic axons were also associated with the large blood vessels of the hippocampal fissure and were present within the hilar region of the dentate gyrus. NGF immunoreactivity was present within the sympathetic axons as well as within glial cells in the transgenic cerebellum and hippocampus. Wild type mice, however, lacked similar patterns of immunostaining. These results demonstrate that elevated expression of NGF in the intact mammalian brain results in the growth of sympathetic axons into the central nervous system in the absence of injury.