Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.

Abstract

The effects of intermale aggressive behavior induced by social isolation on the level of nerve growth factor (NGF) mRNA and protein were investigated in central and peripheral mouse tissues. A large increase in NGF mRNA and protein was observed in hypothalamus, with no changes in cerebral cortex, hippocampus, and cerebellum. No change in NGF mRNA levels was found in heart, spleen, vas deferens, and submaxillary salivary gland. The cellular localization of NGF mRNA in the central nervous system was investigated by in situ hybridization. Numerous nerve cells were specifically labeled in preoptic and ventrolateral nuclei of the hypothalamus, as well as in the cornu ammonis region of the hippocampus and throughout all layers of the cerebral cortex, with the highest concentration in layer III. The present results firmly establish that nerve cells constitute the major source of NGF in the brain. They also open the way to understanding the regulation of NGF biosynthesis in the central nervous system. Nerve growth factor (NGF) is a protein required for the development and maintenance of sympathetic neurons and the majority of neural crest-derived sensory nerve cells (1). It functions as a retrograde trophic messenger between target tissues and their innervating nerve cells. Accordingly, NGF mRNA has been detected in peripheral tissues of various mammalian species (2, 3), whereas NGF receptor mRNA is mostly produced by the corresponding sensory and sympathetic ganglia (4). The actions of NGF are not limited to the peripheral nervous system. Both NGF and its receptor are produced throughout the central nervous system of various mammalian species (4-13) and NGF is retrogradely axonally transported from neocortex and hippocampus to basal forebrain magnocellular cholinergic nerve cells (14,15), where it exerts trophic actions (16-18). Moreover, the degeneration of basal forebrain neurons observed following transection of the septohippocampal pathway is markedly reduced by NGF (19-21). These results suggest that NGF may function as a retrograde trophic messenger for basal forebrain cholinergic nerve cells. However, the widespread occurrence of NGF mRNA throughout the central nervous system suggests additional functions.Whereas a great deal of information is available about the sites of synthesis of NGF in the central nervous system and about some of its biological actions, relatively little is known about the factors regulating NGF synthesis. Aloe et al. (22) showed that intermale aggressive behavior in mice induced by social isolation leads to a marked release of biologically active NGF from the submaxillary salivary gland into the bloodstream. We now report that the same behavioral paradigm leads to a large and specific increase in NGF mRNA and protein in the hypothalamus, where NGF mRNA was found in nerve cells by in situ hybridization. Part of this work has been presented in abstract form. § MATERIALS AND METHODS Behavioral Studies. Male mice of a Swiss-derived (CD-1) strain, with previous breeding experience, w...

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