Interaction of steroid hormones and growth factors in maintaining brain function

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The objectives of the present study were to elucidate molecular mechanisms underlying the actions of steroid hormones and growth factors in maintaining brain function. We first assessed cell proliferation in the dentate gyrus and the mRNA expression levels of granulin, insulin-like growth factor-I (IGF-I), and brain-derived neurotrophic factor (BDNF) in the hippocampus after treatment with estrogen in ovariectomized rats. We found that mRNA expression of granulin precursor and cell proliferation were increased by estrogen treatment, although the mRNA expressions of IGF-I and BDNF remained unchanged. In addition, estrogen enhanced the proliferation of neural progenitor cells derived from hippocampal tissue female rats in vitro, which was inhibited by neutralization of granulin with specific antibody. These results suggest that estrogen induces granulin gene expression in the hippocampus and that the product of this gene is involved in the mitogenic effects of estrogen in the dentate gyrus. We then generated a line of mice with targeted disruption of the granulin gene, and investigated male sexual behaviour, aggression and anxiety. Granulin-deficient mice exhibited a decrease in ejaculation incidence, while the latency and frequency of both mount and intromission were unchanged. Granulin-deficient mice also exhibited enhanced aggressiveness. In wild-type mice, males exhibited lower levels of anxiety than females, while male granulin-deficient mice exhibited an elevated level of anxiety and sex difference in anxiety was not observed. These results suggest that granulin gene plays a role in establishing some kinds of sexual dimorphic behaviours. Finally, we demonstrated that glucocorticoids whose secretion is increased in response to stress play a role in preventing the detrimental effect of stress on nigral dopaminergic neurons and resulting bradykinesia, as well as GnRH pulse generator activity, by suppressing the synthesis of prostaglandins in the brain.