Steroid-induced Neuroplasticity in the Brain

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Work in this laboratory focuses on the effects of stress and gonadal steroids in the brain. 1. Although it has been known for more than 30 years that repeated stress can induce dramatic remodelling of hippocampal pyramidal neuron apical dendrites, particularly in the CA3 sub-field, there has been a relative paucity of studies on the effects of short term, transient stress. We have found that in males, but not females, a single surgical event produces a dramatic reduction in the length of apical CA3 pyramidal neuron dendrites, detectable up to two months later. The effects of orchidectomy differ from those of sham operation, suggesting a stress x testosterone interaction; and are not reproduced by transiently increasing circulating glucocorticoid concentrations, via exposure to the synthetic glucocorticoid dexamethasone in the drinking water, which elicits only a transient truncation of CA3 dendritic branching. We hypothesize that that the lasting dendritic remodelling observed after surgery involves both the initial surgery-associated activation of adrenal glucocorticoid secretion and subsequent inflammation/repair associated responses. To test this hypothesis, we will examine the morphological effects in rats of an initial brief glucocorticoid exposure, with or without subsequent experimentally-induced inflammation. 2. At the cellular level, stress down-regulates expression of dual specificity phosphatase 6 (DUSP6), an androgen-regulated ERK-specific phosphatase. Interestingly, the primary metabolite of testosterone in the brain, 5 androstane 3 17 diol (Adiol) reverses the effects of stress on DUSP6, within the range of circulating Adiol concentrations found in normal males. In females, effects of stress appear to involve different mechanisms, acting in part via glucocorticoid inhibition of G protein coupled estrogen receptor (GPER) signaling. We will examine the effects of stress and glucocorticoid treatment in vivo, with or without concomitant gonadal steroid exposure, in terms of the expression and activity of DUSP6, GPER and related stress-regulated proteins. We will explore the hypothesis that stress and gonadal steroids interact in regulating miRNA expression in the brain. 3. Man-made chemicals in the environment may mimic hormone action, thereby disrupting the behaviors that animals need for survival. We previously reported that one of the most widely used chemicals in the world, bisphenol A (BPA), impairs estrogen induced synaptogenesis in the hippocampus at very low dose levels. Under tissue culture conditions, we have found that BPA is a potent antagonist of GPER activation in the brain, producing a stress-like inhibition of neuronal GPER signaling. We will compare BPA's effects to those of commonly used BPA alternatives, whose effects on the brain have so far not been tested, correlating the in vivo effects of these compounds on GPER signaling with their effects on hippocampal neuronal morphology and cognitive behavior.