In our earlier studies of regional cerebral blood flow using PET, we reported for the first time in humans that induced hypogonadism was associated with the elimination of the normal pattern of cortical activation in the dorsolateral prefrontal cortex (DLPFC);whereas both estradiol and progesterone replacement restored the normal pattern of cortical activation during a working memory task. We are pursuing our original findings that ovarian steroids modulate prefrontal cortical activity in women by augmenting older gold-standard imaging techniques (i.e., O15 PET), in which the technology is relatively stable over time and the activation task paradigms are kept relatively constant over the long-term course of these studies, with newer hypothesis-driven, cutting edge task paradigms and analytic approaches (i.e., fMRI). We employ several different activational paradigms as well as resting state measures during the neuroimaging procedures that will allow us to test neural circuits and interregional functional connectivity relevant to the phenomenology of affective disorders (i.e., prefrontal cortical function, reward system). For example, using the N-back task with two functional imaging methods (PET with repeated scans and fMRI), we are determining the activation pattern for each woman at each hormonal phase to test for variance in their sites of activation. We have completed studies in over 50 asymptomatic women. Preliminary results from our O15 PET studies, demonstrate that estradiol significantly increases resting regional cerebral blood flow (rCBF) activity in regions of the default networks: medial prefrontal cortex (mPFC) and posterior cingulate compared with the hypogonadal state;whereas, progesterone significantly increases resting rCBF in the medial orbital frontal cortex (mOFC) and putamen compared with the hypogonadal state. Our findings that estradiol and progesterone regulate activities within mPFC and mOFC, respectively, have implications for understanding the potential impacts of both estradiol and progesterone on affective-adaptation and stress-responsivity. Preclinical studies have demonstrated that these brain areas are sites at which the effects of sex and sex-steroids modulate the effects of stress on brain function and behavior. Finally, recent data has documented the influence of genotype on cognitive performance and affective-adaptation. We now have identified for the first time in humans significant interactions between sex steroids and variations in specific genes regulated by ovarian steroids (i.e., catechol-o-methyl transferase (COMT) and brain-derived neurotrophic factor (BDNF)) on measures of task-activated regional cerebral blood flow. Estradiol mitigates the effect of COMT genotype on DLPFC activation during the N-back task and estradiol interacts with BDNF genotype to regulate the pattern of activation in the hippocampus during the N-back task. We previously demonstrated changes in reward-related neurocircuitry across the normal menstrual cycle with increased activations during the expectancy of the reward during the follicular phase, when estradiol levels are high. These data demonstrate, for the first time in humans, that ovarian steroids modulate reward system function, with increased follicular phase activation of the orbitofrontal cortex and amygdala during reward anticipation and of the midbrain, striatum, and left ventrolateral prefrontal cortex (VLPFC) during reward delivery. We have further investigated these finding across the menstrual cycle by employing the reward paradigm in women who are participating in the GnRH agonist-induced hypogonadism study in which we examine the effects of estradiol and progesterone separately compared with a hypogonadal state. Preliminary findings demonstrate that both estradiol and progesterone modulate reward-related neurocircuitry. During the anticipation of reward, estradiol increased activity in the amygdala and orbitofrontal cortex compared with the hypogonadal state (consistent with our previous data across the menstrual cycle), and progesterone increased activity within the right inferior frontal gyrus compared with both estradiol and hypogonadism. These data suggest a substrate in which changes in gonadal steroids could modulate affective state, and are consistent with preclinical studies that document the modulatory effects of ovarian steroids on reward-related behaviors and brain regions, as well as a growing literature demonstrating the importance of the reward system in depression. Finally, we have measured grey matter (GM) volume using structural MRI scans across the menstrual cycle and under pharmacologically controlled hormonal conditions. GM volume in the hippocampus increased during the luteal compared with the follicular phase of the menstrual cycle and during progesterone addback compared with both estradiol and hypogonadism. In our previous studies of the effects of gonadal steroids on stress responsivity, we identified that progesterone rather than estradiol has a greater impact on HPA axis activation in humans, unlike in rodents, but the response to progesterone appears to differ in women with PMD and controls. We have conducted dexamethasone-corticotrophin releasing hormone (Dex/CRH) testing in women with PMD and controls in both menstrual cycle and Lupron studies. We have completed a study of 43 women employing Dex/CRH studies. Our data confirm a progesterone-related enhancement of HPA axis function despite dex inhibition, whereas no effects of estradiol on HPA axis function were evident (see Annual Report for project MH002865-06). There has been a widespread presumption in clinical neuroscience that ovarian steroids regulate 5HT transport function leading to sex and sex steroid-related differences in affective adaptation. We employ the 5HT transporter ligand DASB during both naturalistic and experimentally-induced conditions to examine claims that ovarian steroids are important physiological regulators of the 5HT transporter. We have completed a study of 5HT transport function across the menstrual cycle, and are about to complete a similar study in examining 5HT transport function during pharmacologically controlled hormonal conditions. These data will be the first to characterize the effects of sex steroids on5HT transporter function in the human brain, and will either confirm or seriously question the physiologic relevance of the widely embraced assumption that ovarian steroid-related modulations of 5HT function underlie both many of the observed sex-differences in affective disorders and reproductive endocrine-related mood disorders including postpartum and perimenopausal depressions.

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Dubey, N; Hoffman, J F; Schuebel, K et al. (2017) The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry 22:1172-1184
Guerrieri, Gioia M; Wakim, Paul G; Keenan, P A et al. (2016) Sex differences in visuospatial abilities persist during induced hypogonadism. Neuropsychologia 81:219-29
Martinez, Pedro E; Rubinow, David R; Nieman, Lynnette K et al. (2016) 5?-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder. Neuropsychopharmacology 41:1093-102
Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C et al. (2016) Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol 6:1135-60
Schmidt, Peter J; Ben Dor, Rivka; Martinez, Pedro E et al. (2015) Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. JAMA Psychiatry 72:714-26
Schiller, Crystal Edler; Schmidt, Peter J; Rubinow, David R (2014) Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology (Berl) 231:3557-67
Baller, Erica B; Wei, Shau-Ming; Kohn, Philip D et al. (2013) Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study. Am J Psychiatry 170:305-14
Schmidt, Peter J; Keenan, P A; Schenkel, Linda A et al. (2013) Cognitive performance in healthy women during induced hypogonadism and ovarian steroid addback. Arch Womens Ment Health 16:47-58
Ben Dor, Rivka; Harsh, Veronica L; Fortinsky, Paige et al. (2013) Effects of pharmacologically induced hypogonadism on mood and behavior in healthy young women. Am J Psychiatry 170:426-33
Miller, Alexandra; Vo, Hoa; Huo, Liang et al. (2010) Estrogen receptor alpha (ESR-1) associations with psychological traits in women with PMDD and controls. J Psychiatr Res 44:788-94

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