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The mediation of lesion-induced sprouting in the nervous system is a complex interaction of local membrane factors and circulating hormones. This series of studies examines the reactivity of the sprouting response of both male and female subjects under different hormonal conditions. Young adult male and female Sprague-Dawley rats which were gonadectomized (GDX) and adrenalectomized (ADX) underwent a unilateral entorhinal cortex lesion, which partially denervates the molecular layer of the ipsilateral hippocampal dentate gyrus. At the time of the lesion, each animal received hormonal therapy. Fifteen days post-ERC-ab-lation the brains were analyzed for changes in reactive fiber outgrowth in the hippocampal commissural/associational afferents. Fiber outgrowth in females in the “asteroidal” ( GDX ADX ) condition was unaffected. Asteroidal males demonstrated a decreased response. Gonadal steroid replacement, estrogen or testosterone, enhanced outgrowth in both asteroidal males and females. Glucocorticoid replacement suppressed outgrowth in both asteroidal males and females. Gonadal steroids clearly have neurotrophic activity which is interactive with glucocorticoid activity. Glucocorticoids under the GDX ADX conditions in vivo have a negative impact on fiber outgrowth in both sexes. The effect of glucocorticoids is most dramatic when compared to the outgrowth of asteroidal animals without additional hormonal supplementation.

Adrenalectomy protects hippocampal pyramidal cells from transient ischemia in rats. We hypothesized that this effect of adrenalectomy could be generalized to the gerbil. We determined the effect of glucocorticoid manipulation on hippocampal CA1 cell death following transient forebrain ischemia in the gerbil. Adrenalectomy diminished hippocampal damage when performed immediately following transient forebrain ischemia, as in the rat, while glucocorticoid administration resulted in an increase in CA1 pyramidal cell damage. Furthermore adrenalectomy 24 h after the ischemic injury diminished hippocampal damage to roughly the same extent as immediate adrenalectomy. However, if gerbils were examined at longer survival periods after ischemia, the difference in hippocampal damage between adrenalectomized and sham-adrenalectomized was lost. These findings suggest that glucocorticoids influence the rate of hippocampal pyramidal cell disappearance following ischemia. Manipulation of glucocorticoids could be an important adjunct to therapy for preventing ischemic brain damage.

Young adult Sprague-Dawley rats of either sex were randomly assigned to be gonadectomized or left intact. Capsules containing either testosterone or estrogen were implanted in animals in both categories. Fifteen days after removal of the entorhinal cortex, the brains were analyzed for changes in reactive outgrowth of the commissural-associational afferent fibers in the hippocampal dentate gyrus. Both male and female control subjects showed identical sprouting responses. Only female subjects were significantly affected by gonadectomy, resulting in significant decreases in reactive fiber outgrowth. Hormone replacement therapy resulted in a return to control values in castrated females but had no affect on castrated males. The results suggest that sex hormones may regulate axon sprouting in the mature central nervous system.

Young adult male and female Sprague-Dawley rats were randomly assigned to be gonadectomized (GDX), adrenalectomized (ADX), gonadectomized and adrenalectomized (GDX/ADX) or left intact. One week following initial surgery all animals were subjected to a lesion of the entorhinal cortex (ERC) which partially denervates the ipsilateral hippocampal dentate gyrus. Fifteen days after the ERC ablation, the brains were analyzed for changes in reactive outgrowth of the hippocampal commissural-associational (C-A) afferents. Under intact conditions there were no differences between male and female subjects. Female subjects demonstrated a suppression of sprouting following GDX alone and an enhancement of growth following ADX alone. Reactive growth in male subjects was unaffected by GDX or ADX alone. When placed in the ‘asteroidal’ (GDX/ADX) condition, reactive outgrowth of male subjects in significantly impaired as compared to female subjects. The results suggest a complex inter-relationship between the gonadal and adrenal hormones and a possible neurotrophic effect for the gonadal steroids.

Hydrocortisone was administered to young adult male or female rats after removal of the entorhinal cortex. Lesion-induced outgrowth of the commissural-associational afferent fibers in the hippocampus was quantitated. The glucocorticoids caused a significant decline in axon sprouting in the male subjects and a significant increase in outgrowth in female subjects. Depending on the sex, the hormonal effects on lesion-induced axonal growth are markedly different in the rat.