Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

LC-MS/MS measurement of endogenous oxytocin in the posterior pituitary and CSF of macaques: A pilot study.

Oxytocin (OT) is a nanopeptide released into systemic circulation via the posterior pituitary (peripheral) and into the central nervous system via widespread OTergic pathways (central). Central OT plays a significant role in variety of functions from social and executive cognition to immune regulation. Many ongoing studies explore its therapeutic potential for variety of neuropsychiatric disorders. Measures of peripheral OT levels are most frequently used as an indicator of its concentration in the central nervous system in humans and animal models. In this study, LC-MS/MS was used to measure OT in pituitary samples collected from adult male macaque monkeys in order to explore the correlation between individual levels of OT in the CSF (central) and pituitary (peripheral). We quantified individual differences in the levels of OT in the pituitaries (44-151 ng/mg) and CSF (41-66 pg/mL) of these monkeys. A positive correlation between these two measures was identified. These preliminary results allow for future analyses to determine whether LC-MS/MS measures of peripheral OT can be used as markers of OT levels in the brain of nonhuman primates that serve as valuable models for many human neuropsychiatric disorders.

Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques.

Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated. In this nonhuman primate study, we administer deuterated oxytocin intranasally and intravenously to rhesus macaques and measure, with mass spectrometry, concentrations of labeled (exogenously administered) and endogenous oxytocin in 12 brain regions two hours after oxytocin administration. Labeled oxytocin is quantified after intranasal (not intravenous) administration in brain regions (orbitofrontal cortex, striatum, brainstem, and thalamus) that lie in the trajectories of the olfactory and trigeminal nerves. These results suggest that intranasal administration bypasses the blood-brain barrier, delivering oxytocin to specific brain regions, such as the striatum, where oxytocin acts to impact motivated behaviors. Further, high concentrations of endogenous oxytocin are in regions that overlap with projection fields of oxytocinergic neurons.

Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential.

CONTEXT: Endometrium in polycystic ovary syndrome (PCOS) presents altered gene expression indicating progesterone resistance and predisposing to reduced endometrial receptivity and endometrial cancer. OBJECTIVE: We hypothesized that an altered endocrine/metabolic environment in PCOS may result in an endometrial "disease phenotype" affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny. DESIGN AND SETTING: This was a prospective study conducted at an academic medical center. PATIENTS AND MAIN OUTCOME MEASURES: Proliferative-phase endometrium was obtained from 6 overweight/obese PCOS (National Institutes of Health criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting-isolated endometrial epithelial cells (eEPs), endothelial cells, stromal fibroblasts (eSFs), and mesenchymal stem cells (eMSCs). Gene expression data were validated using microfluidic quantitative RT-PCR and immunohistochemistry. RESULTS: The comparison between eEP(PCOS) and eEP(Ctrl) showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSF(PCOS) and eSF(Ctrl) showed up-regulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSC(PCOS) vs eMSC(Ctrl), the most up-regulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). Immunohistochemistry scoring showed increased expression of CCL2 in eEP(PCOS) and eSF(PCOS) compared with eEP(Ctrl) and eSF(Ctrl) and IL-6 in eEP(PCOS) compared with eEP(Ctrl). CONCLUSIONS: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and prooncogenic changes, independent of body mass index, especially in eEP(PCOS) and eMSC(PCOS), compared with controls. The study reveals an endometrial disease phenotype in women with PCOS with potential negative effects on endometrial function and long-term health.