The Neuroregulatory Effects of Gonadal Steroids in Humans

National Institute Of Mental Health

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Abstract

This report includes work arising from the following clinical protocols: NCT00026832, NCT00100360, NCT00001177, and NCT00001322. Evidence suggests that genomic variation in sex-steroid receptors or in the systems regulated by sex steroids may contribute to the ovarian hormone-sensitivity observed in PMDD. Thus, as a first step, we examined the effects of common genetic variations in women during each of the hormonal conditions established within the GnRH agonist-induced hypogonadism and ovarian steroid addback protocol. We have tested two specific, common functional variants (BDNF Val66Met and COMT Val158Met) that are both regulated by sex steroids and that are known to alter brain function in specific brain regions including the hippocampus and prefrontal cortex, respectively. In our studies, therefore, we employ these gene variants as probes for the impact of genetic substrates on the effects of ovarian steroids on womens brain function. A post hoc sensitivity analysis demonstrated that the effects of both BDNF and COMT genotypes were only evident in the presence of estradiol, and the differences in WM-related rCBF were brain region-specific: the effects of COMT genotype were only observed in the DLPFC regardless of the BDNF genotype, whereas the differences in rCBF between the BDNF genotype were confined to the hippocampus regardless of the COMT genotype. Overall, the findings from these studies demonstrate that in women, variations in genes putatively regulated by ovarian steroids impact functional neurocircuitry in a brain-region- and hormone-specific manner here, specifically, interactions between BDNF and COMT genotypes and estradiol on the activation of functional neurocircuitry in the hippocampus (where BDNF is highly expressed) and the DLPFC (where COMT has primacy for dopamine trafficking), respectively. Although sex steroids display pleiotropic effects within the CNS, their actions are often tissue-specific and reflect the effects of local tissue-specific regulators that facilitate sex steroid signaling in one tissue and inhibit or repress the signal in another tissue. Our findings demonstrate how genetic context could modulate the regulatory actions of sex steroids on the functions of specific brain regions involved in the pathophysiology of neuropsychiatric conditions, including the PFC and hippocampus. Additionally, these data suggest that effects of genes or hormones may not be identified if examined in isolation, given the impact of their interactions. Finally, we will probe the roles of variation in sex steroid-regulated genes on brain development across puberty, a time when the brain is re-exposed to sex steroids at gonadarche. In a separate study in which we examined presynaptic dopamine synthesis capacity in thirty-one healthy, regularly menstruating women, who underwent 18F-FDOPA PET scanning. Eleven women were scanned during the follicular phase and twenty women during the luteal phase. We documented increased 18F-FDOPA uptake in the follicular relative to luteal phase in bilateral striatum, including left putamen and right ventral striatum. Overall. we observed greater 18F-FDOPA uptake in women assessed during epochs of the menstrual cycle associated with relatively higher estradiol levels (follicular vs. luteal phase). These results align with prior preclinical and human studies demonstrating estradiols modulatory effects on DA function, and, if confirmed in longitudinal samples, may provide direction for future studies on neuropsychiatric disorders in women. Our functional genomic studies in cell lines from both women with and without PMDD and those with and without PPD have pursued our initial findings of altered function of the ESC/E(Z) gene complex in PMDD as follows: First, neuroprogenitor cells (NPCs) were successfully differentiated from induced pluripotent stem cells (iPSCs) made from women with PMDD and control women (confirmed by immunofluorescent staining and transcriptome analysis).Both LCLs and NPCs show signatures of differential gene silencing through similar mechanisms at baseline and in response to ovarian steroids. These findings in NPCs reveal neuronal differences between women with PMDD and controls both at baseline and after ovarian steroids, including ESC/E(Z) targets. Second, we examined the effects of a 24-hr dose of allopregnanolone (ALLO) on the GABAergic system gene expression in lymphoblastoid cell lines (LCLs) derived from patients with postpartum depression (PPD, n=8) and controls (n=6). Findings demonstrated differential expression of several genes including GABAR2, a GABA receptor, and GAD1, which synthesizes GABA. Pathway analysis revealed that the 24-hr ALLO exposure affected pathways involved in cell signaling, protein processing, and transcription. These data further inform our understanding of the potential mechanisms involved in the effects of brexanolone (ALLO) in mood disorders including PPD. We also are currently performing a study in which cultured iPSC lines from patients with PMDD and controls, that will be differentiated into neural stem cells (which will later be further differentiated into glutamatergic and dopaminergic neurons) to examine the effects of ALLO on these important neurotransmitter systems. In parallel, in the coming year, we will use single-nucleus sequencing to examine the effects of ALLO on gene expression in several regions of the mouse brain implicated in mood disorders and motivation (such as the striatum, hippocampus, amygdala, and prefrontal cortex). Finally, we have completed a high-density longitudinal study of women as they transition through the menopause. Our previous studies demonstrated the absence of an effect of acute loss of ovarian steroid exposure (i.e., hypogonadism) in younger premenopausal women. We now confirm a similar pattern of effects with no differences in cognitive performance in older women as they transition across the menopause. We will examine individual differences in menopause-related changes in cognition; however, the group as a whole demonstrates the lack of impact of the menopause transition in healthy, non-depressed women in the setting of ovarian aging.