Epigenomic organization and activation of brain sex differences

The “Organizational-Activational Hypothesis”, the central dogma of neuroendocrinology, states that early-life (“organizational”) and adult (“activational”) gonadal hormone signaling drives sex differences in the mammalian brain. Early-life hormones irreversibly sculpt the development of the same neural circuits that adult hormones act upon to promote the display of sex-typical behaviors. Gonadal hormones bind nuclear hormone receptors, which principally act as transcription factors (TFs). Hence, the regulation of gene expression by hormone receptors in the brain comprises the molecular basis of the “Organizational-Activational Hypothesis”, and, accordingly, ensures the survival and propagation of most mammalian species. However, the genomic targets of gonadal hormone receptors in the brain, and their regulation during “organizational” and “activational” windows, have not been identified. Here, I utilize low-input and single-cell chromatin and transcriptomic profiling approaches to identify the genomic mechanisms specifying sex differences in the developing and adult mouse bed nucleus of the stria terminalis (BNST) – a central brain region in the limbic circuitry controlling sextypical behaviors. I find that male-specific activation of estrogen receptor α (ERα) on the day of birth drives sustained sex differences in gene regulation in the developing brain. Subsequently, testosterone (T) largely controls sex differences in gene regulation following puberty. Of note, adult gonadectomy ablates sex differences in chromatin accessibility, while estradiol (E2) replacement after gonadectomy leads to sex-shared genomic responses, revealing brain “organization” by early-life hormone signaling is reversible at the level of gene regulation. Together, I reveal the first genomic targets of a gonadal hormone receptor in the brain and define the molecular principles of the “Organizational-Activational Hypothesis”. I provide a compendia of sex-biased enhancers, genes, and neuron types across life stages that serve the basis for future functional investigation into the genomic encoding of social behavior

Pacific Portraits: The People Behind the Scenes at Pacific University (Volume One)

When a dormitory toilet is clogged, who’s the guy charged with fixing it? Who assures that benefits and work-study monies are paid and accounted for on time? And who is tasked with ensuring Luau goes off without a hitch or that students from Saudi Arabia know how to navigate the cultural idiosyncrasies of an American university? Meet the people who work behind the scenes at Pacific University—the community of staff and faculty—as captured by Pacific’s own creative writing and photography students. Their jobs and lives are varied, but their dedication to ensuring a dynamic educational experience in all its varieties is common between them. This book strives to capture and share their stories through the creative efforts of the students their work serves.https://commons.pacificu.edu/beetree/1001/thumbnail.jp

Epigenetic Mechanisms of Brain Sexual Differentiation

Across vertebrate species, gonadal hormones coordinate physiology with behavior to facilitate social interactions essential for reproduction and survival. In adulthood, these hormones activate neural circuits that regulate behaviors presenting differently in females and males, such as parenting and territorial aggression. Yet long before sex-typical behaviors emerge at puberty, transient hormone production during sensitive periods of neurodevelopment establish the circuits upon which adult hormones act. How transitory waves of early-life hormone signaling exert lasting effects on the brain remains a central question. Here we discuss how perinatal estradiol signaling organizes cellular and molecular sex differences in the rodent brain. We review classic anatomic studies revealing sex differences in cell number, volume, and neuronal projections, and consider how single-cell sequencing methods enable distinction between sex-biased cell-type abundance and gene expression. Finally, we highlight the recent discovery of a gene regulatory program activated by estrogen receptor α (ERα) following the perinatal hormone surge. A subset of this program displays sustained sex-biased gene expression and chromatin accessibility throughout the postnatal sensitive period, demonstrating a bona fide epigenetic mechanism. We propose that ERα-expressing neurons throughout the social behavior network use similar gene regulatory programs to coordinate brain sexual differentiation

Oxytocin receptor behavioral effects and cell types in the bed nucleus of the stria terminalis

Oxytocin is a neuropeptide that can produce anxiolytic effects and promote social approach. However, emerging evidence shows that under some conditions, oxytocin can instead induce anxiety-related behaviors. These diverse effects of oxytocin appear to be mediated by circuit-specific actions. Recent data showed that inhibition of oxytocin receptors (OTRs) in the bed nucleus of the stria terminalis (BNST) was sufficient to increase social approach and decrease social vigilance in female California mice (Peromyscus californicus) exposed to social defeat stress. As a member of the G-protein coupled receptor family, OTRs can induce distinct downstream pathways by coupling to different G-protein isoforms. We show that infusion of carbetocin, a biased OTR-Gq agonist, in the BNST reduced social approach in both female and male California mice. In both females and males, carbetocin also increased social vigilance. To gain insight into cell types that could be mediating this effect, we analyzed previously published single-cell RNAseq data from the BNST and nucleus accumbens (NAc). In the NAc, we and others showed that OTR activation promotes social approach behaviors. In the BNST, Oxtr was expressed in over 40 cell types, that span both posterior and anterior subregions of the BNST. The majority of Oxtr-expressing neurons were GABAergic. In the anterior regions of BNST targeted in our carbetocin experiments, Cyp26b1-expressing neurons had high average Oxtr expression. In the NAc, most Oxtr+ cells were D1 dopamine receptor-expressing neurons and interneurons. These differences in Oxtr cell type distribution may help explain how activation of OTR in BNST versus NAc can have different effects on social approach and social vigilance

Oestrogen engages brain MC4R signalling to drive physical activity in female mice.

Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes1,2, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17β-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3-7 projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity8 - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women9. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes