A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior.

Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.

Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior.

Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with ∼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.

Considering Organismal Physiology in Laboratory Studies of Rodent Behavior.

Any experiment conducted in a rodent laboratory is done so against the backdrop of each animal's physiological state at the time of the experiment. This physiological state can be the product of multiple factors, both internal (e.g., animal sex, strain, hormone cycles, or circadian rhythms) and external (e.g., housing conditions, social status, and light/dark phases). Each of these factors has the potential to influence experimental outcomes, either independently or via interactions with others, and yet there is little consistency across laboratories in terms of the weight with which they are considered in experimental design. Such discrepancies-both in practice and in reporting-likely contribute to the perception of a reproducibility crisis in the field of behavioral neuroscience. In this review, we discuss how several of these sources of variability can impact outcomes within the realm of common learning and memory paradigms.

Different Effects of Peer Sex on Operant Responding for Social Interaction and Striatal Dopamine Activity.

When rats are given discrete choices between social interactions with a peer and opioid or psychostimulant drugs, they choose social interaction, even after extensive drug self-administration experience. Studies show that like drug and nondrug food reinforcers, social interaction is an operant reinforcer and induces dopamine release. However, these studies were conducted with same-sex peers. We examined if peer sex influences operant social interaction and the role of estrous cycle and striatal dopamine in same- versus opposite-sex social interaction. We trained male and female rats (n = 13 responders/12 peers) to lever-press (fixed-ratio 1 [FR1] schedule) for 15 s access to a same- or opposite-sex peer for 16 d (8 d/sex) while tracking females' estrous cycle. Next, we transfected GRAB-DA2m and implanted optic fibers into nucleus accumbens (NAc) core and dorsomedial striatum (DMS). We then retrained the rats for 15 s social interaction (FR1 schedule) for 16 d (8 d/sex) and recorded striatal dopamine during operant responding for a peer for 8 d (4 d/sex). Finally, we assessed economic demand by manipulating FR requirements for a peer (10 d/sex). In male, but not female rats, operant responding was higher for the opposite-sex peer. Female's estrous cycle fluctuations had no effect on operant social interaction. Striatal dopamine signals for operant social interaction were dependent on the peer's sex and striatal region (NAc core vs DMS). Results indicate that estrous cycle fluctuations did not influence operant social interaction and that NAc core and DMS dopamine activity reflect sex-dependent features of volitional social interaction.

Transcriptomic Analysis of Pubertal and Adult Virgin Mouse Mammary Epithelial and Stromal Cell Populations.

Conflicting data exist as to how mammary epithelial cell proliferation changes during the reproductive cycle. To study the effect of endogenous hormone fluctuations on gene expression in the mouse mammary gland, we performed bulk RNAseq analyses of epithelial and stromal cell populations that were isolated either during puberty or at different stages of the adult virgin estrous cycle. Our data confirm prior findings that proliferative changes do not occur in every mouse in every cycle. We also show that during the estrous cycle the main gene expression changes occur in adipocytes and fibroblasts. Finally, we present a comprehensive overview of the Wnt gene expression landscape in different mammary gland cell types in pubertal and adult mice. This work contributes to understanding the effects of physiological hormone fluctuations and locally produced signaling molecules on gene expression changes in the mammary gland during the reproductive cycle and should be a useful resource for future studies investigating gene expression patterns in different cell types across different developmental timepoints.

Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress.

The estrous cycle is a potent modulator of neuron physiology. In rodents, in vivo ventral tegmental area (VTA) dopamine (DA) activity has been shown to fluctuate across the estrous cycle. Although the behavioral effect of fluctuating sex steroids on the reward circuit is well studied in response to drugs of abuse, few studies have focused on the molecular adaptations in the context of stress and motivated social behaviors. We hypothesized that estradiol fluctuations across the estrous cycle acts on the dopaminergic activity of the VTA to alter excitability and stress response. We used whole-cell slice electrophysiology of VTA DA neurons in naturally cycling, adult female C57BL/6J mice to characterize the effects of the estrous cycle and the role of 17ß-estradiol on neuronal activity. We show that the estrous phase alters the effect of 17ß-estradiol on excitability in the VTA. Behaviorally, the estrous phase during a series of acute variable social stressors modulates subsequent reward-related behaviors. Pharmacological inhibition of estrogen receptors in the VTA before stress during diestrus mimics the stress susceptibility found during estrus, whereas increased potassium channel activity in the VTA before stress reverses stress susceptibility found during estrus as assessed by social interaction behavior. This study identifies one possible potassium channel mechanism underlying the increased DA activity during estrus and reveals estrogen-dependent changes in neuronal function. Our findings demonstrate that the estrous cycle and estrogen signaling changes the physiology of DA neurons resulting in behavioral differences when the reward circuit is challenged with stress.SIGNIFICANCE STATEMENT The activity of the ventral tegmental area encodes signals of stress and reward. Dopaminergic activity has been found to be regulated by both local synaptic inputs as well as inputs from other brain regions. Here, we provide evidence that cycling sex steroids also play a role in modulating stress sensitivity of dopaminergic reward behavior. Specifically, we reveal a correlation of ionic activity with estrous phase, which influences the behavioral response to stress. These findings shed new light on how estrous cycle may influence dopaminergic activity primarily during times of stress perturbation.

The uterine secretory cycle: recurring physiology of endometrial outputs that setup the uterine luminal microenvironment.

Conserved in female reproduction across all mammalian species is the estrous cycle and its regulation by the hypothalamic-pituitary-gonadal (HPG) axis, a collective of intersected hormonal events that are crucial for ensuring uterine fertility. Nonetheless, knowledge of the direct mediators that synchronously shape the uterine microenvironment for successive yet distinct events, such as the transit of sperm and support for progressive stages of preimplantation embryo development, remain principally deficient. Toward understanding the timed endometrial outputs that permit luminal events as directed by the estrous cycle, we used Bovidae as a model system to uniquely surface sample and study temporal shifts to in vivo endometrial transcripts that encode for proteins destined to be secreted. The results revealed the full quantitative profile of endometrial components that shape the uterine luminal microenvironment at distinct phases of the estrous cycle (estrus, metestrus, diestrus, and proestrus). In interpreting this comprehensive log of stage-specific endometrial secretions, we define the "uterine secretory cycle" and extract a predictive understanding of recurring physiological actions regulated within the uterine lumen in anticipation of sperm and preimplantation embryonic stages. This repetitive microenvironmental preparedness to sequentially provide operative support was a stable intrinsic framework, with only limited responses to sperm or embryos if encountered in the lumen within the cyclic time period. In uncovering the secretory cycle and unraveling realistic biological processes, we present novel foundational knowledge of terminal effectors controlled by the HPG axis to direct a recurring sequence of vital functions within the uterine lumen.NEW & NOTEWORTHY This study unravels the recurring sequence of changes within the uterus that supports vital functions (sperm transit and development of preimplantation embryonic stages) during the reproductive cycle in female Ruminantia. These data present new systems knowledge in uterine reproductive physiology crucial for setting up in vitro biomimicry and artificial environments for assisted reproduction technologies for a range of mammalian species.

Estradiol and progesterone in female reward-learning, addiction, and therapeutic interventions.

Sex steroid hormones like estradiol (E2) and progesterone (P4) guide the sexual organization and activation of the developing brain and control female reproductive behavior throughout the lifecycle; importantly, these hormones modulate functional activity of not just the endocrine system, but most of the nervous system including the brain reward system. The effects of E2 and P4 can be seen in the processing of and memory for rewarding stimuli and in the development of compulsive reward-seeking behaviors like those seen in substance use disorders. Women are at increased risk of developing substance use disorders; however, the origins of this sex difference are not well understood and therapeutic interventions targeting ovarian hormones have produced conflicting results. This article reviews the contribution of the E2 and P4 in females to functional modulation of the brain reward system, their possible roles in origins of addiction vulnerability, and the development and treatment of compulsive reward-seeking behaviors.

A missed opportunity: A scoping review of the effect of sex and age on osteoarthritis using large animal models.

OBJECTIVE: The objective was to critically analyze the published literature accounting for sex differences and skeletal age (open vs. closed physis) in preclinical animal models of OA, including the disaggregation of data by sex and skeletal maturity when data is generated from combined sex and/or multi-aged cohorts without proper confounding. METHOD: A scoping literature review of PubMed, Web of Science, EMBASE, and SCOPUS was performed for studies evaluating the effect of sex and age in experimental studies and clinical trials utilizing preclinical large animal models of OA. RESULTS: A total of 9727 papers were identified in large animal (dog, pig, sheep, goat, horse) models for preclinical OA research, of which 238 ex vivo and/or in vivo studies disclosed model type, animal species, sex, and skeletal age sufficient to analyze their effect on outcomes. Dogs, followed by pigs, sheep, and horses, were the most commonly used models. A paucity of preclinical studies evaluated the effect of sex and age in large animal models of naturally occurring or experimentally induced OA: 26 total studies reported some kind of analysis of the effects of sex or age, with 4 studies discussing the effects of sex only, 11 studies discussing the effects of age only, and 11 studies analyzing both the effects of age and sex. CONCLUSION: Fundamental to translational research, OARSI is uniquely positioned to develop recommendations for conducting preclinical studies using large animal models of OA that consider biological mechanisms linked to sex chromosomes, skeletal age, castration, and gonadal hormones affecting OA pathophysiology and treatment response.

Disruptions in reproductive health, sex hormonal profiles, and hypothalamic hormone receptors content in females of the C58/J mouse model of autism.

Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.

Beyond the binary: Characterizing the relationships between sex and neuropeptide receptor binding density measures in the rat brain.

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints.

Generalization of a positive-feature interoceptive morphine occasion setter across the rat estrous cycle.

INTRODUCTION: Interoceptive stimuli elicited by drug administration acquire conditioned modulatory properties of the induction of conditioned appetitive behaviours by exteroceptive cues. This effect may be modeled using a drug discrimination task in which the drug stimulus is trained as a positive-feature (FP) occasion setter (OS) that disambiguates the relation between an exteroceptive light conditioned stimulus (CS) and a sucrose unconditioned stimulus (US). We previously reported that females are less sensitive to generalization of a FP morphine OS than males, so we investigated the role of endogenous ovarian hormones in this difference. METHODS: Male and female rats received intermixed injections of 3.2 mg/kg morphine or saline before each daily training session. Training consisted of 8 presentations of the CS, each followed by access to sucrose on morphine, but not saline sessions. Following acquisiton, rats were tested for generalization of the morphine stimulus to 0, 1.0, 3.2, and 5.4 mg/kg morphine. Female rats were monitored for estrous cyclicity using vaginal cytology throughout the study. RESULTS: Both sexes acquired stable drug discrimination. A gradient of generalization was measured across morphine doses and this behaviour did not differ by sex, nor did it differ across the estrous cycle in females. CONCLUSIONS: Morphine generalization is independent of fluctuations in levels of sex and endogenous gonadal hormones in females under these experimental conditions.

Evaluation of the vaginal and urinary microbiota of healthy cycling bitches.

BACKGROUND: While the urogenital microbiota has recently been characterized in healthy male and female dogs, the influence of sex hormones on the urogenital microbiome of bitches is still unknown. A deeper understanding of the cyclic changes in urinary and vaginal microbiota would allow us to compare the bacterial populations in healthy dogs and assess the impact of the microbiome on various urogenital diseases. Therefore, the aim of this study was to characterize and compare the urogenital microbiota during different phases of the estrous cycle in healthy female dogs. DNA extraction, 16 S rDNA library preparation, sequencing and informatic analysis were performed to determine the vaginal and urinary microbiota in 10 healthy beagle dogs at each phase of the estrous cycle. RESULTS: There were no significant differences in alpha and beta diversity of the urinary microbiota across the different cycle phases. Similarly, alpha diversity, richness and evenness of vaginal bacterial populations were not significantly different across the cycle phases. However, there were significant differences in vaginal beta diversity between the different cycle phases, except for between anestrus and diestrus. CONCLUSION: This study strongly suggests that estrogen influences the abundance of the vaginal microbiota in healthy female dogs, but does not appear to affect the urinary microbiome. Furthermore, our data facilitate a deeper understanding of the native urinary and vaginal microbiota in healthy female dogs.

Correlation between microbial characteristics and reproductive status of the yak uterus based on macrogenomic analysis.

INTRODUCTION: This study aimed to investigate the microbial characteristics of yak uteri collected using intrauterine cotton swabs (CS) during different reproductive stages and the correlation of these microbial characteristics with reproductive status. METHODS: We used a macrogenomic approach to analyze the functional aspects of different microorganisms in samples collected during the pre-estrus, estrus, late estrus, and diestrus stages. RESULTS: The results revealed the presence of 1293 microbial genera and 3401 microbial species in the uteri of yaks at different reproductive stages. The dominant bacterial species varied across the different periods, with Micrococcus and Proteus being dominant during pre-estrus; Pseudomonas, Clostridium, Flavobacterium, Bacillus, and Staphylococcus during estrus; Acinetobacter, Bacillus and Proteus during late estrus; and Pseudomonas, Escherichia coli, and Proteus during diestrus. DISCUSSION: The primary functions of these bacteria are enriched in various metabolic pathways, including carbohydrate and amino acid metabolism, intracellular transport and secretion, post-translational protein modification, and drug resistance. These findings suggest that the microbial diversity in the uterus of yaks plays a crucial role in reproductive regulation and can help prevent reproductive tract-related diseases.

Histological, immunohistochemical and serological investigations of the ovary during follicular phase of estrous cycle in Saidi sheep.

BACKGROUND: Saidi sheep are the most abundant ruminant livestock species in Upper Egypt, especially in the Assiut governorate. Sheep are one of the most abundant animals raised for food in Egypt. They can convert low-quality roughages into meat and milk in addition to producing fiber and hides therefore; great opportunity exists to enhance their reproduction. Saidi breed is poorly known in terms of reproduction. So this work was done to give more information on some hormonal, oxidative, and blood metabolites parameters in addition to histological, histochemical and immunohistochemical investigations of the ovary during follicular phase of estrous cycle. The present study was conducted on 25 healthy Saidi ewes for serum analysis and 10 healthy ewes for histological assessment aged 2 to 5 years and weighted (38.5 ± 2.03 kg). RESULTS: The follicular phase of estrous cycle in Saidi sheep was characterized by the presence of ovarian follicles in different stages of development and atresia in addition to regressed corpus luteum. Interestingly, apoptosis and tissue oxidative markers play a crucial role in follicular and corpus luteum regression. The most prominent features of the follicular phase were the presence of mature antral (Graafian) and preovulatory follicles as well as increased level of some blood metabolites and oxidative markers. Here we give a new schematic sequence of ovarian follicles in Saidi sheep and describing the features of different types. We also clarified that these histological pictures of the ovary was influenced by hormonal, oxidative and blood metabolites factors that characterizes the follicular phase of estrous cycle in Saidi sheep. CONCLUSION: This work helps to understanding the reproduction in Saidi sheep which assist in improving the reproductive outcome of this breed of sheep. These findings are increasingly important for implementation of a genetic improvement program and utilizing the advanced reproductive techniques as estrous synchronization, artificial insemination and embryo transfer.

Parallel expression patterns of NR4A nuclear receptor family genes in the pituitary gland of proestrus rats.

The NR4A nuclear receptor family (NR4As), encompassing NR4A1, NR4A2, and NR4A3, exerts pivotal roles in cellular processes through intricate expression patterns and interactions. Despite the influence of some NR4As on anterior pituitary functions regulated by the hypothalamus, their physiological expression patterns remain unclear. In our prior work, we demonstrated the specific upregulation of NR4A3 in the rat anterior pituitary gland during the proestrus afternoon, coinciding with a gonadotropin surge. In this study, we investigated changes in pituitary Nr4a gene expression throughout the estrous cycle in rats and a gonadotropin surge-induced model. Nr4a1 and Nr4a2 gene expression significantly increased during proestrus, aligning with previous observations for Nr4a3. Furthermore, prolactin gene expression increased sequentially with rising Nr4a gene expression, while thyroid-stimulating hormone beta gene expression remained stable. Immunohistochemistry revealed a widespread and differential distribution of NR4A proteins in the anterior pituitary, with NR4A1 and NR4A3 being particularly abundant in thyrotrophs, and NR4A2 in gonadotrophs. In estrogen-treated ovariectomized rats, elevated luteinizing hormone secretion corresponded to markedly upregulated expression of Nr4a1, Nr4a2, and Nr4a3. In gonadotroph and somatomammotroph cell lines, gonadotropin- and thyrotropin-releasing hormones transiently and dose-dependently increased the expression of Nr4a genes. These findings suggest that hypothalamic hormone secretion during proestrus may induce the parallel expression of pituitary Nr4a genes, potentially influencing the pituitary gene expression program related to endocrine functions before and after ovulation.

Differential effects of high-fat diet on endocrine, metabolic and depressive-like behaviors in male and female rats.

The complications of obesity extend beyond the periphery to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Preclinical studies support this concept, including studies that have examined the effects of a high-fat diet (HFD) on depressive-like behaviors. Although women are approximately two-fold more likely to develop depressive illness compared to men, most preclinical studies have focused on the effects of HFD in male rodents. Accordingly, the goal of this study was to examine depressive-like behaviors in male and female rats provided access to a HFD. In agreement with prior studies, male and female rats provided a HFD segregate into an obesity phenotype (i.e., diet-induced obesity; DIO) or a diet resistant (DR) phenotype. Upon confirmation of the DR and DIO phenotypes, behavioral assays were performed in control chow, DR, and DIO rats. In the sucrose preference test, male DIO rats exhibited significant decreases in sucrose consumption (i.e., anhedonia) compared to male DR and male control rats. In the forced swim test (FST), male DIO rats exhibited increases in immobility and decreases in climbing behaviors in the pre-test sessions. Interestingly, male DR rats exhibited these same changes in both the pre-test and test sessions of the FST, suggesting that consumption of a HFD, even in the absence of the development of an obesity phenotype, has behavioral consequences. Female rats did not exhibit differences in sucrose preference, but female DIO rats exhibited increases in immobility exclusively in the test session of the FST, behavioral changes that were not affected by the stage of the estrous cycle. Collectively, these studies demonstrate that access to a HFD elicits different behavioral outcomes in male and female rats.

Is prolonged luteal phase a problem in lactating Holstein cows?

In this study, the main objective was to assess if long luteal phases could have other causes than pregnancy losses. We enrolled Holstein dairy cows ≥50 d in milk (DIM) from a commercial herd in Brazil from October 2016 to August 2017. All cows received an estradiol-based synchronization protocol, and, on the day of insemination (d 0), were randomly assigned either an artificial insemination (AI) or a placebo insemination (PBO) in a 3:1 ratio. An ultrasound was used to assess the presence of a CL on d17, 24, and 31, which, combined to the information from patches for the detection of estrus, was used to determine the length of the luteal phase following AI or PBO. Pregnancy was assessed by ultrasound on d 31 and cows that were pregnant were excluded from the analyses. The length of the estrous cycles was categorized as short (<17 d), normal (17-23 d), long (24-30 d), and very long (≥31 d). We compared the proportion of cows in each category between the AI and PBO groups using a cumulative ordinal mixed model. We define prolonged luteal phase as estrous cycles ≥24 d and tested its association with potential risk factors (parity, season, DIM, uterine size and position score, milk production, body condition score, and the presence of a corpus luteum (CL) at enrollment to the synchronization protocol) using mixed logistic regression models. Results are presented as odds ratio (OR) and 95% credible intervals (BCI). Data from 876 inseminations (AI: n = 616, PBO: n = 260) was collected. Overall, 12% of estrous cycles were short, 31% were normal, 19% were long, and 38% were very long. There was no difference in the odds of being in longer estrous cycle categories for the AI compared with the PBO group (OR = 0.92, 95% BCI = 0.76-1.10). Season and presence of a CL at enrollment were associated with prolonged luteal phase. In the AI group, there was a possible effect of early pregnancy losses on the lifespan of the CL, but not the PBO group, which led us to conclude that long and very long estrous cycles were not all caused by the embryonic loss. In fact, the high prevalence of cows with an extended CL lifespan in the present study suggests this could be an under- or miss-reported characteristic of high-producing lactating Holstein cows. This finding may have important repercussions in the understanding of the CL function physiology of lactating Holstein cows.

Can animal models resemble a premenstrual dysphoric condition?

Around 80% of women worldwide suffer mild Premenstrual Disorders (PMD) during their reproductive life. Up to a quarter are affected by moderate to severe symptoms, and between 3% and 8% experience a severe form. It is classified as premenstrual syndrome (PMS) with predominantly physical symptoms and premenstrual dysphoric disorder (PMDD) with psychiatric symptoms. The present review analyzes the factors associated with PMD and the Hypothalamus-Pituitary-Ovarian or Hypothalamus-Pituitary-adrenal axis and discusses the main animal models used to study PMDD. Evidence shows that the ovarian hormones participate in PMDD symptoms, and several points of regulation of their synthesis, metabolism, and target sites could be altered. PMDD is complex and implies several factors that require consideration when this condition is modeled in animals. Of particular interest are those points related to areas that may represent opportunities to develop new approximations to understand the mechanisms involved in PMDD and possible treatments.

Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms.

Women are at twice the risk for anxiety and depression disorders as men are, although the underlying biological factors and mechanisms are largely unknown. In this review, we address this sex disparity at both the etiological and mechanistic level. We dissect the role of fluctuating sex hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. We provide parallel evidence in humans and rodents that brain structure and function vary with naturally-cycling ovarian hormones. This female-unique brain plasticity and associated vulnerability are primarily driven by estrogen level changes. For the first time, we provide a sex hormone-driven molecular mechanism, namely chromatin organizational changes, that regulates neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. Finally, we map out future directions including experimental and clinical studies that will facilitate novel sex- and gender-informed approaches to treat depression and anxiety disorders.