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Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Fatty acids (FAs) are important for cell membrane composition, eicosanoid synthesis, and metabolic processes. Membrane proteins that facilitate FA transport into cells include FA translocase (also known as CD36) and FA transporter proteins (encoded by SLC27A genes). The present study aimed to examine expression profiles of FA transporters in the endometrium of cyclic and early pregnant gilts on days 3 to 20 after estrus and the possible regulation by conceptus signals and polyunsaturated FAs (PUFAs). The effect of PUFAs on prostaglandin (PG) synthesis and transcript abundance of genes related to FA action and metabolism, angiogenesis, and immune response was also determined. Day after estrus and reproductive status of animals affected FA transporter expression, with greater levels of CD36, SLC27A1, and SLC27A4 observed in pregnant than in cyclic gilts. Conceptus-conditioned medium and/or estradiol-17β stimulated SLC27A1 and CD36 expression. Among PUFAs, linoleic acid decreased SLC27A1 and SLC27A6 mRNA expression, while arachidonic, docosahexaenoic, and eicosapentaenoic acids increased SLC27A4 transcript abundance. Moreover, arachidonic acid stimulated ACOX1, CPT1A, and IL1B expression and increased PGE2 and PGI2 secretion. In turn, α-linolenic acid up-regulated VEGFA, FGF2, FABP4, and PPARG mRNA expression. These results indicate the presence of an active transport of FAs in the porcine endometrium and the role of PUFAs as modulators of the uterine activity during conceptus implantation. [ABSTRACT FROM AUTHOR]

AbstractAlpha-terpineol (α-T) is a type of monoterpenoid alcohol commonly present in essential oils, it contributes to a pleasant floral fragrance similar to that of lilacs. This research aimed to evaluate the impact of α-terpineol on the reproductive functions of both male and female rats, including gonadal activity, mating behavior, conception, conceptus development and parturition. Six male and female Wistar rats per group received α-terpineol through gavage at doses of 0, 75, 150 and 300 mg/kg/day. The study revealed changes in body weight gain inhibition, food consumption, azoospermia, decreased testosterone levels (0.7 ± 1.61 ng/mL, 0.7 ± 2.30 ng/mL) as well as histopathological variations in testis and epididymis among males exposed to doses of 150 and 300 mg/kg/day. Moreover, this exposure led to significantly decreased serum T4 levels in both adult males (21.85 ± 12.68 ng/mL, 16.20 ± 9.15 ng/mL) and dams (11.24 ± 12.37 ng/mL, 9.48 ± 11.74 ng/mL) at the dose range of 150 and 300 mg/kg/day without affecting TSH concentrations. In summary, the present study showed that α-terpineol induced reproductive toxicities in male rats. Therefore, a detailed toxicological assessment is highly recommended. [ABSTRACT FROM AUTHOR]

The recurrent hormonal fluctuations within reproductive cycles impact sleepwake behavior in women and in rats and mice used in preclinical models of sleep research. Strides have been made in sleep-related clinical trials to include equal numbers of women; however, the inclusion of female rodents in neuroscience and sleep research is lacking. Female animals are commonly omitted from studies over concerns of the effect of estrus cycle hormones on measured outcomes. This review highlights the estrous cycle's broad effects on sleep-wake behavior: from changes in sleep macroarchitecture to regionally specific alterations in neural oscillations. These changes are largely driven by cycle-dependent ovarian hormonal fluctuations occurring during proestrus and estrus that modulate neural circuits regulating sleep-wake behavior. Removal of estrous cycle influence by ovariectomy ablates characteristic sleep changes. Further, sex differences in sleep are present between gonadally intact females and males. Removal of reproductive hormones via gonadectomy in both sexes mitigates some, but not all sex differences. We examine the extent to which reproductive hormones and sex chromosomes contribute to sex differences in sleep-wake behavior. Finally, this review addresses the limitations in our understanding of the estrous cycle's impact on sleep-wake behavior, gaps in female sleep research that are well studied in males, and the implications that ignoring the estrous cycle has on studies of sleep-related processes. [ABSTRACT FROM AUTHOR]

Successful identification of estrum or other stages in a cycling bitch often requires a combination of methods, including assessment of its behavior, exfoliative vaginal cytology, vaginoscopy, and hormonal assays. Vaginoscopy is a handy and inexpensive tool for the assessment of the breeding period. The present study introduces an innovative method for identifying the stages in the estrous cycle of female canines. With a dataset of 210 vaginoscopic images covering four reproductive stages, this approach extracts deep features using the inception v3 and Residual Networks (ResNet) 152 models. Binary gray wolf optimization (BGWO) is applied for feature optimization, and classification is performed with the extreme gradient boosting (XGBoost) algorithm. Both models are compared with the support vector machine (SVM) with the Gaussian and linear kernel, k-nearest neighbor (KNN), and convolutional neural network (CNN), based on performance metrics such as accuracy, specificity, F1 score, sensitivity, precision, matthew correlation coefficient (MCC), and runtime. The outcomes demonstrate the superiority of the deep model of ResNet 152 with XGBoost classifier, achieving an average model accuracy of 90.37%. The method gave a specific accuracy of 90.91%, 96.38%, 88.37%, and 88.24% in predicting the proestrus, estrus, diestrus, and anestrus stages, respectively. When performing deep feature analysis using inception v3 with the same classifiers, the model achieved an accuracy of 89.41%, which is comparable to the results obtained with the ResNet model. The proposed model offers a reliable system for identifying the optimal mating period, providing breeders and veterinarians with an efficient tool to enhance the success of their breeding programs. [ABSTRACT FROM AUTHOR]

Abstract Successful identification of estrum or other stages in a cycling bitch often requires a combination of methods, including assessment of its behavior, exfoliative vaginal cytology, vaginoscopy, and hormonal assays. Vaginoscopy is a handy and inexpensive tool for the assessment of the breeding period. The present study introduces an innovative method for identifying the stages in the estrous cycle of female canines. With a dataset of 210 vaginoscopic images covering four reproductive stages, this approach extracts deep features using the inception v3 and Residual Networks (ResNet) 152 models. Binary gray wolf optimization (BGWO) is applied for feature optimization, and classification is performed with the extreme gradient boosting (XGBoost) algorithm. Both models are compared with the support vector machine (SVM) with the Gaussian and linear kernel, k-nearest neighbor (KNN), and convolutional neural network (CNN), based on performance metrics such as accuracy, specificity, F1 score, sensitivity, precision, matthew correlation coefficient (MCC), and runtime. The outcomes demonstrate the superiority of the deep model of ResNet 152 with XGBoost classifier, achieving an average model accuracy of 90.37%. The method gave a specific accuracy of 90.91%, 96.38%, 88.37%, and 88.24% in predicting the proestrus, estrus, diestrus, and anestrus stages, respectively. When performing deep feature analysis using inception v3 with the same classifiers, the model achieved an accuracy of 89.41%, which is comparable to the results obtained with the ResNet model. The proposed model offers a reliable system for identifying the optimal mating period, providing breeders and veterinarians with an efficient tool to enhance the success of their breeding programs.

BACKGROUND: The rat estrous cycle first characterized by Long and Evans in 1922 profoundly affected the course of endocrine research. Investigators took advantage of sex steroid hormone fluctuations associated with the cycle to assess hormonal influences on anxiety, depression, food intake, stress, brain structure and other traits. Similarities of the rat estrous and human menstrual cycles facilitated understanding of human reproductive physiology. I assessed the impact of awareness of the estrous cycle on the emergence of a sex bias that excluded female rats from biomedical research. METHODS: Beginning with the 1918 volume of the American Journal of Physiology and ending in 1976 when the journal subdivided into several separate disciplinary journals, all studies conducted on rats were downloaded; the use of females, males, both sexes and sex left unspecified was tabulated for 485 articles. A second analysis tracked the number of rat estrous cycle studies across all disciplines listed in PubMed from 1950 to 2021. RESULTS: The description and awareness of variability associated with the rat estrous cycle was correlated with a precipitous decline in investigations that incorporated both sexes, a marked increase in male-only studies and a striking sex bias that excluded female rats. The number of rat estrous cycles studies increased markedly from earlier decades to a peak in 2021. CONCLUSIONS: The initial description the rat estrous cycle was correlated with a substantial decline in investigations that incorporated both sexes; one result was a marked increase in male-only studies and a striking sex bias that excluded female rats from biomedical research. Recognition of the advantages of studies that incorporate the rat estrous cycle has resulted in recent years in an increase of such investigations. Female rats and females of several other species are not more variable than their male counterparts across traits, arguing for female inclusion without requiring cycle monitoring. There, remain, however, many advantages of incorporating the estrous cycle in contemporary research.

Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.

Abstract 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.

Background and Aim: Vaginal cytology is an effective method for assessing the activity of the hypothalamus-pituitary-ovary axis in rodents. This study aimed to investigate the restoration of ovarian function following the transplantation of vitrified ovarian tissue by examining daily vaginal smears. Methods: In this experimental study, 20 adult female NMRI mice (8 weeks old) with regular estrous cycles were randomly divided into four groups: a control group, an ovariectomy group, a vitrified ovarian transplant (VT) group, and a non-vitrified ovarian transplant (FT) group. All groups, except the control group, underwent ovariectomy. In the VT group, the right ovary was auto-transplanted into the muscle of the same mouse after vitrification and thawing. In the FT group, the right ovary was auto-transplanted into the muscle of the same mouse without vitrification. From the fourth day after transplantation until the end of the second estrous cycle, daily vaginal smears were collected. The onset of the first proestrus in each mouse indicated the beginning of the estrous cycle, and the interval between two consecutive proestrus phases was considered a complete cycle. Results: All transplants in both the VT and FT groups were completely successful. The mean onset of the first and second estrous cycles in the VT group was significantly delayed compared to the FT and control groups (P

Highlights: 1. This study found that Leucaena leucocephala leaf ethanol extract has the ability to stimulate the growth of vaginal epithelial cells in ovariectomised rats. 2. Leucaena leucocephala leaf extract can be developed as a safe and cost-effective natural alternative for hormone replacement therapy in premenopausal women and livestock. Highlights: 1. This study found that Leucaena leucocephala leaf ethanol extract has the ability to stimulate the growth of vaginal epithelial cells in ovariectomised rats. 2. Leucaena leucocephala leaf extract can be developed as a safe and cost-effective natural alternative for hormone replacement therapy in premenopausal women and livestock. Abstract Hormone replacement therapy has adverse effects that may cause additional health problems, such as hot flashes, cancer, ischemic stroke, and death. Phytoestrogen is an alternative ingredient used for hormone replacement therapy with less risk. The Leucaena leucocephala (Lam.) de Wit plant is widely used as a medicinal ingredient and animal feed. This study aimed to determine the effect of Leucaena leucocephala leaf extract on the uterine weight and estrous cycle of ovariectomized rats. This research used a completely randomized control design, which included two treatment groups (P1 and P2) and two control groups (negative (K-) and positive (K+)) with six replications in each group (n=24). The negative control (K-) was given 2 mL of corn oil, while K+ received 0.1 mg/kg bw of 17β-estradiol. P1 and P2 were administered 250 and 300 mg/kg bw of Leucaena leucocephala leaf extract, respectively. The extract was administered daily by gavage for 30 days. Estrous cycle data were obtained on day 31 by previously collecting vaginal swabs twice a day for 15 days. After the rats were sacrificed under anesthesia using chloroform, they underwent surgery to remove the uterine organs for weight measurement. The data were analyzed for normality and homogeneity using the Shapiro-Wilk and Levene tests. The data distribution were not normal, so the Kruskal Wallis test was used to test the hypothesis. If there was a difference between controls and treatments, the analysis continued with the Mann-Whitney test (p

Abstract Background Abrus precatorious is a member of the leguminous family with characteristic red and black seeds. The roots, leaves and seeds of this plant are used for different medicinal purpose. It principally carries flavonoids, triterpene glycosides, abrin and alkaloids. The plant had been mentioned for neuromuscular effects, neuro-protective, abortifacient, antiepileptic, anti-viral, antimalarial, antifertility, nephroprotective, immunomodulator, immunostimulatory properties, antiinflammatory activity, antidiabetic, and many others. The aim of this study was to investigate the anti-fertility activity of the methanol extract of Abrus precatorius seeds (APS) in female albino rats administered 45 and 50 mg/kg BW through oral gavage for 30 days. An Abrus precatorius seed (APS) was extracted (1:1 w/v) using methanol to obtain the crude extract. Liquid-liquid fractionation was performed on the crude methanol extract using solvents of different polarity. Methods Eighteen female rats were divided into three groups each containing six animals was used for this experiment. Group one (control), received 1 ml of saline solution, group two received 45 mg/kg and group three received 50 mg/kg body weight by oral gavage daily for a period of 30 days. At the end of the study, Body weight, Organ Weight, Estrous cycle, Hormonal Concentrations, Oxidative Stress Markers, Enzymatic Activities, Biochemical indices (Liver and Kidney panel) and Hematological parameters were also evaluated. Results Consequent upon the administration of A.precatorius seed methanol extract 45 and 50 mg/kg BW into the female rats resulted in changes pertaining to Body weight, Estrous cycle, Hormonal Concentrations, Antioxidant Enzymes, Serum Biochemical indices and Hematological indices significantly (p

Background: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated. Methods: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases. Results: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase. Conclusions: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the serum iron status and its relation to hematological indexes in cyclic mares. Blood samples were taken from 40 Spanish Purebred mares on days − 5, 0, + 5 and + 16 of their cycle. Concentration of transferrin (TRF) was significantly lower on day 0 than on days + 5 and + 16, transferrin saturation (TSAT) decreased significantly on days 0 and + 16 compared to day − 5, total iron-binding capacity (TIBC) on day + 16 was significantly higher than those on days − 5 and 0, and on day + 5 it was also significantly higher than that on day 0, unsaturated iron-binding capacity (UIBC) was reduced on day + 16 compared to days − 5 and 0, red blood cell (RBC) count on day + 16 was higher than that on days − 5 and 0 (p < 0.05), with no differences in the concentration of hemoglobin (HB) and packed cell volume (PCV). TRF and TIBC (r = 0.95), RBC and HB (r = 0.64), RBC and PCV (r = 0.78), and HB and PCV (r = 0.63) were positively and significantly correlated (P < 0.05). The estrous cycle in the Spanish Purebred mare is characterized by an increase in TRF and TIBC during the follicular phase and an increase in TSAT, UIBC and RBC in the luteal phase, without changes in other hematological parameters. The coordinated activity of these parameters guarantees an adequate iron (Fe) transfer and utilization during follicular development, ovulation, and the luteal period in the mare. Therefore, the estrous cycle must be considered in the evaluation of the mare's iron status, in light of significant changes observed both in early and at late luteal phases. The magnitude of these changes and the meaning to the physiology of the mares showed that in cyclic mares, hematological parameters and indicators of iron status evolve differently depending on the phase of the cycle, and their interpretation can help to veterinarians involved in equine practice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Seizures and epilepsy affect people of all sexes and genders. In the last several years, funding agency initiatives such as the U.S. National Institutes of Health policy on sex as a biological variable (SABV) have intended to encourage researchers to study both males and females from cell to tissue to organism and analyze and report the resulting data with sex as a factor. Preclinical epilepsy research, however, continues to be plagued by confusion regarding both the SABV policy and its implementation, reflecting similar beliefs in the larger neuroscience research community. This article aims to address some common misconceptions and provide practical tools and suggestions for preclinical epilepsy researchers in implementing SABV and analysis of the female ovarian cycle (estrous cycle in rodents) in their research programs, with a focus on studies using rodent models. Examples of recent publications in preclinical epilepsy research highlighting the value of incorporating SABV and information on the estrous cycle are included. The specifics of how best to address SABV and the estrous cycle can vary depending on the needs and goals of a particular research program, but an embrace of these physiological factors by the preclinical epilepsy research community promises to yield more rigorous research and improved treatment strategies for all people with epilepsy. [ABSTRACT FROM AUTHOR]

The obesity epidemic continues to increase, with half of US women predicted to be obese by 2030. Women with obesity are at increased risk for not only cardiovascular and liver disease, but also reproductive disorders. Although mouse models are useful in studying the effects of obesity, there is inconsistency in obesity-induction methods, diet composition, and mouse strains, and studies using female mice are limited. In this study, we sought to compare the effects of a 45% high-fat diet (HFD) versus a 60% HFD on the uterine estrous cycle of nulligravid C57BL/6J mice. For 22 weeks, we placed a total of 20 mice on either a 60% HFD, 45% HFD, or each HFD-matched control diet (CD). Both HFDs produced significant weight gain, with 60% HFD and 45% HFD gaining significant weight after 2 weeks and 15 weeks, respectively. Additionally, both HFDs led to glucose intolerance, fatty liver, and adipocyte hypertrophy. Mice fed 60% HFD displayed hyperphagia in the first 12 weeks of HFD treatment. Moreover, 60% HFD-treated mice had a longer estrous cycle length and an increased percentage of estrus stage samplings compared to CD-treated mice. Estrous cycle stage-controlled 60% HFD-treated mice displayed an increased estrogen-to-progesterone ratio and decreased ovarian corpora lutea compared to CD-treated mice, which may underlie the observed estrous cycle differences. There was no significant difference between diets regarding endometrial morphology or the percent of endometrial CD45+ immune cells. Our results indicate that consideration is needed when selecting a HFD-induced obesity mouse model for research involving female reproductive health. [ABSTRACT FROM AUTHOR]

Background: Abrus precatorious is a member of the leguminous family with characteristic red and black seeds. The roots, leaves and seeds of this plant are used for different medicinal purpose. It principally carries flavonoids, triterpene glycosides, abrin and alkaloids. The plant had been mentioned for neuromuscular effects, neuro-protective, abortifacient, antiepileptic, anti-viral, antimalarial, antifertility, nephroprotective, immunomodulator, immunostimulatory properties, antiinflammatory activity, antidiabetic, and many others. The aim of this study was to investigate the anti-fertility activity of the methanol extract of Abrus precatorius seeds (APS) in female albino rats administered 45 and 50 mg/kg BW through oral gavage for 30 days. An Abrus precatorius seed (APS) was extracted (1:1 w/v) using methanol to obtain the crude extract. Liquid-liquid fractionation was performed on the crude methanol extract using solvents of different polarity. Methods: Eighteen female rats were divided into three groups each containing six animals was used for this experiment. Group one (control), received 1 ml of saline solution, group two received 45 mg/kg and group three received 50 mg/kg body weight by oral gavage daily for a period of 30 days. At the end of the study, Body weight, Organ Weight, Estrous cycle, Hormonal Concentrations, Oxidative Stress Markers, Enzymatic Activities, Biochemical indices (Liver and Kidney panel) and Hematological parameters were also evaluated. Results: Consequent upon the administration of A.precatorius seed methanol extract 45 and 50 mg/kg BW into the female rats resulted in changes pertaining to Body weight, Estrous cycle, Hormonal Concentrations, Antioxidant Enzymes, Serum Biochemical indices and Hematological indices significantly (p < 0.05) compared to control rats. Initial body weights are significantly (p < 0.05) indicated, whereas final weights were decreased significantly (p < 0.05). Organ weight changes i.e. Ovary, Liver and Kidney weights were found to be significantly (p < 0.05) decreased in APS administered rats compared to control. Estrous cycle study i.e. time duration of Proestrus, Estrus, Metestrus and Diestrus (in days) was significantly prolonged. Hormonal Concentrations represented by FSH, LH, Prolactin, Estradiol were significantly (p < 0.05) decreased, whereas Progesterone levels were significantly (p < 0.05) increased in APS administered female rats compared to control group of rats. All the antioxidant enzyme assayed CAT, SOD, GPx, GR and GST were found to be significantly (p < 0.05) decreased, whereas MDA concentration was found to be increased significantly (p < 0.05). Enzymatic activities and biomolecules includes Cholesterol and Ascorbic acid contents were significantly increased (p < 0.05), but G6PDH and Δ5 − 3β-HSD activities were found to be significantly (p < 0.05) decreased in APS administered group of female rats compared to control group. Biochemical indices of liver tissue presented by Bilirubin, SGPT, SGOT, Albumin and Globulin were found to be significantly (p < 0.05) increased whereas Alkaline Phosphate and Total Protein contents were found to be significantly (p < 0.05) decreased. The biochemical indices of kidney, i.e. Urea and Creatinine were significantly (p < 0.05) increased and Uric acid and Calcium contents were found to be significantly (p < 0.05) decreased in APS administered female rats compared to control group of rats. Hematological parameters including RBC, Hb, ESR and Clotting Time were found to be significantly (p < 0.05) increased but WBC levels were significantly (p < 0.05) increased in APS administered female rats compared to control group of rats. Conclusion: A. Precatorius seeds have anti-fertility effect on female rats. [ABSTRACT FROM AUTHOR]

Current rodent models of anorexia nervosa (AN) often have accelerated weight loss that often do not allow for investigation of physiological ramifications of prolonged low weight status characteristic of AN. The purpose of this project was to refine a rodent model of AN to extend the duration of low weight status and allow for investigation of recovery. Eight‐week‐old female Sprague Dawley rats underwent 50%–60% food restriction for 30 days. Rats were group‐housed except during feeding, where AN rats were individually housed and given up to 2 h to consume food. Control (CON) rats were allowed to consume food ad libitum. To simulate recovery, a separate cohort of animals underwent the same food restriction protocol for 30 days, then rats (AN‐R) were allowed to consume food ad libitum to facilitate weight recovery for an additional 30 days. AN‐R rats were compared to age matched controls (CON‐R). AN rats lost ~15% bodyweight and were ~30% lighter than CON. Compared to CON, AN rats had ~35% lower fat content, ~18% lower bone mineral density, ~22% smaller plantaris muscle mass and ~52% smaller ovaries. Upon reintroduction of food, AN‐R rats achieved comparable bodyweights to CON‐R rats after ~10 days. However, after 30 days of recovery, AN‐R rats still had ~14% lower bone mineral density and ~11% smaller plantaris mass and ~21% smaller ovaries. This refinement of rodent AN results in physiological side effects of AN without reaching excessive weight loss requiring euthanasia. Moreover, some physiological consequences of simulated AN are not resolved with weight restoration. [ABSTRACT FROM AUTHOR]

Metanil yellow (MY) is a widely used colour additive to impart yellow or orange hues in food items to make it more attractive to consumers. Previous studies have shown that MY can put a negative impact to our health and various physiologic parameters. In this study we have tried to demonstrate a detailed effect of MY consumption during gestation period as well as lactation period within rats by using Wister albino rat as an experimental model. We have found that increased consumption of MY through various food sources can interfere with oxygen carrying capacity of blood to various tissues. Liver and kidneys are largely affected among the vital organs due to increased catalase activity (which can generate ROS) within those tissues. We observed shortened estrous cycles within MY treated groups. The pups of MY treated rats have shown stunted growth when compared to control group. [ABSTRACT FROM AUTHOR]

IntroductionIncreasing evidence indicates that sex is a factor that impacts the abuse liability and relapse vulnerability of prescription opioids like oxycodone. However, while women are more likely than men to be prescribed and to use these drugs, the impact of sex and ovarian hormones on prescription opioid use and relapse vulnerability remains unclear. Accurately assessing these measures is complicated by the fact that chronic opioid exposure can lower ovarian hormone levels and cause cycle irregularities.MethodsAdult male and female Sprague–Dawley rats self-administered oxycodone (0.1 mg/kg/infusion) under extended-access conditions (6 h/day, 10 days) followed by forced abstinence. Separate groups of animals received cue-induced seeking tests in a drug-free state during early (1–2 days) or later periods of abstinence (43–45 days). To track estrous cycle stage, animals were regularly vaginally swabbed throughout the study.ResultsWe observed oxycodone-induced estrous cycle dysregulation in the majority (~60%) of the animals during both self-administration and the first month of abstinence. In animals whose cycles were not dysregulated, we found a reduction in oxycodone intake during estrus compared to all other cycle stages (non-estrus). We also found that males but not females showed a time-dependent intensification or incubation of cue-induced oxycodone craving over the first 6 weeks of abstinence. This sex difference was estrous cycle-dependent, driven by a selective reduction in drug seeking during estrus.DiscussionThese findings highlight the importance of tracking drug-induced estrous cyclicity and identify a clear impact of ovarian hormones on oxycodone taking and seeking behavior.

Abstract Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.

Pyrethroid insecticides are currently a widely used class of pesticides. It is therefore important to determine the mechanism of disorders in some mammalian systems due to prolonged exposure to these pesticides and to justify means to prevent poisoning complications. The study was conducted on 30 female rats aged 3 months for 120 days. Intoxication was modeled using α-cypermethrin at a dose of 10 mg/kg. The prevention of intoxication complications was carried out with an adaptogenic complex consisting of the flavonoid quercetin, vitamins C and D3, and minerals (Ca, Mn, Zn, Cu, Se, Mg) at a dose of 500 mg/kg. Assessment of intoxication and preventive efficacy of the adaptogen was performed by determining the duration of the estrous cycle, ovarian organ index, degree of atrophy of the alveolar process in the jaws, as well as density, content of mineral and organic components in the bones. Hepatotoxicity markers were determined in the blood serum, osteoresorption markers in the alveolar bone homogenate, inflammation indicators in the liver, and antioxidant system status in all tissues. Prolonged exposure to α-cypermethrin was associated with a prolongation of the estrous cycle due to a reduction in the diestrus stage and a decrease in the ovarian organ index along with a significant increase in blood estradiol levels. In intoxicated animals, the degree of atrophy of the alveolar process increased and the density of femurs and vertebrae decreased due to a decrease in the weight fraction of the mineral component in the bones. In the bone tissue of the alveolar process, an increase in the activity of elastase and markers of oxidative stress (an increase in the content of malondialdehyde and a decrease in catalase activity), as well as a compensatory increase in the alkaline phosphatase activity were found. In the rat liver, an increase in the acid phosphatase activity and the inhibition of antioxidant defense were observed. An increase in the elastase activity and a decrease in the catalase activity with an increase in the malondialdehyde content were found in the serum of the animals. The use of an adaptogen under conditions of α-cypermethrin intoxication contributed to the normalization of the estrous cycle, ovarian organ index and blood estradiol levels. In the tissue of the femur and vertebrae of rats, the treatment by the prophylactic complex led to an increase in bone density due to an increase in the content of the mineral component, and a decrease in the degree of atrophy of the jaws, in the tissue of which the activation of the enzymatic link of antioxidant defense and a decrease in the activity of destructive elastase too were found. The developed adaptogen prevented the development of oxidative stress and inflammation in the blood serum and liver in the animals. The results of the research indicate a negative effect of α-cypermethrin on the sexual function in female rats, on the state of bone tissue along with the hepatotoxic effect of the pesticide. The proposed agent for the prevention of α-cypermethrin intoxication effectively prevented endocrine disruption in the ovaries, bone destruction and inflammation in the liver.

Abstract 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.

The orexin system plays a major role in drug reward. Orexin-1 receptor (OxR1) blockade reduces fentanyl demand in males. However, there are a number of sex differences in the orexin system, and it is unclear how OxR1 antagonism would decrease fentanyl demand in females. Furthermore, the relationships between the estrous cycle and fentanyl intake are yet to be delineated.Here, we conducted a behavioral economics (BE) procedure in female rats to assess the effects of the OxR1 antagonist SB-334867 on fentanyl demand before and after short-(ShA), long- (LgA) or intermittent-access (IntA) self-administration of fentanyl; we also tested the effect of SB-334867 on cued reinstatement of fentanyl seeking. Finally, we measured the impact of the estrous cycle on fentanyl demand, intake and seeking.Results showed that in females SB-334867 did not consistently modulate demand for fentanyl before or after chronic access periods. However, SB-334867 at 30mg/kg reduced the number of active lever presses during cued-reinstatement of fentanyl seeking. We also found that fentanyl self-administration disrupted estrous cyclicity, in particular proestrus epochs, an effect that depended on short versus chronic access. Furthermore, extended access to fentanyl shifted the role of progesterone from facilitation of fentanyl demand during short periods, to attenuation of fentanyl demand after long term exposure. These results indicate that an orexin-based therapy in women for treating opioid use disorder must consider prior drug history as well as cycle phase.

Despite recent work demonstrating that female rodents and humans do not show greater variance in behavior and physiology than males due to ovulatory cycles, many researchers still default to using males in their investigations. Although government funding agencies now require inclusion of female subjects where applicable, the erroneous belief that the study of males reduces overall data variance continues to result in male subject bias. Recently, we reported the first direct experimental refutation of this belief by examining continuous body temperature and locomotor activity in male and female mice. These findings revealed that males exceeded female variance within and across individuals over time, showing greater variance within a day than females do across an entire estrous cycle. However, the possibility remains that male variance within a day is impacted by ultradian rhythms, analogous to the influence of infradian estrous cycles on female variance, and both sexes show predictable, structured variance across the day. If structures underlying variance can be predicted, then the variance can be statistically accounted for, reducing experimental error and increasing precision of measurements. Here we assess these continuous body temperature and activity data for the contributions of structured and unstructured variance to overall variance within and across individuals at ultradian, circadian, and infradian timescales. In no instance do females exceed male variance, and in most instances male variance exceeds female variance. Additionally, more female variance is accounted for by temporal structure. In conclusion, even when estrous cycles are not controlled for, females show less variability than males, and this advantage can be further capitalized upon by inclusion of known temporal patterns to control for previously unknown but structured sources of variance.

Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data. [ABSTRACT FROM AUTHOR]

Context: Extracellular vesicles (EVs) derived from the oviductal fluid (oEVs) play a critical role in various reproductive processes, including sperm capacitation, fertilisation, and early embryo development. Aims: To characterise porcine oEVs (poEVs) from different stages of the estrous cycle (late follicular, LF; early luteal, EL; mid luteal, ML; late luteal, LL) and investigate their impact on sperm functionality. Methods: poEVs were isolated, characterised, and labelled to assess their binding to boar spermatozoa. The effects of poEVs on sperm motility, viability, acrosomal status, protein kinase A phosphorylation (pPKAs), tyrosine phosphorylation (Tyr-P), and in in vitro fertility were analysed. Key results: poEVs were observed as round or cup-shaped membrane-surrounded vesicles. Statistical analysis showed that poEVs did not significantly differ in size, quantity, or protein concentration among phases of the estrous cycle. However, LF poEVs demonstrated a higher affinity for binding to sperm. Treatment with EL, ML, and LL poEVs resulted in a decrease in sperm progressive motility and total motility. Moreover, pPKA levels were reduced in presence of LF, EL, and ML poEVs, while Tyr-P levels did not differ between groups. LF poEVs also reduced sperm penetration rate and the number of spermatozoa per penetrated oocyte (P < 0.05). Conclusions: poEVs from different stages of the estrous cycle play a modulatory role in sperm functionality by interacting with spermatozoa, affecting motility and capacitation, and participating in sperm–oocyte interaction. Implications: The differential effects of LF and LL poEVs suggest the potential use of poEVs as additives in IVF systems to regulate sperm–oocyte interaction. We examined the tiny structures called extracellular vesicles that come from the fluid in pig uterus in order to understand how these vesicles change during the reproductive cycle of female pigs. Those from the late stages of the cycle seemed to have a strong connection with sperm and a possible key role in fertility. These vesicles regulate sperm function and interaction with oocytes, and they could potentially be used in fertility treatments to improve the chances of successful fertilisation. Photograph by SM Toledo-Guardiola. This article belongs to the Collection Dedication to Jim Cummins. [ABSTRACT FROM AUTHOR]

Rationale: Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone. Clinically, chronic cocaine use was correlated with decreased levels of pregnenolone. Preclinically, the effect of acute cocaine on allopregnanolone levels in rodents has had mixed results, showing an increase or no change in allopregnanolone levels in some brain regions. Objective: We hypothesized that cocaine acutely increases allopregnanolone levels, but repeated cocaine exposure decreases allopregnanolone levels compared to controls. Methods: We performed two separate studies to determine how systemic administration of 15 mg/kg cocaine (1) acutely or (2) chronically alters brain (olfactory bulb, frontal cortex, dorsal striatum, and midbrain) and serum allopregnanolone levels in adult male and female Sprague-Dawley rats. Results: Cocaine acutely increased allopregnanolone levels in the midbrain, but not in olfactory bulb, frontal cortex, or dorsal striatum. Repeated cocaine did not persistently (24 h later) alter allopregnanolone levels in any region in either sex. However, allopregnanolone levels varied by sex across brain regions. In the acute study, we found that females had significantly higher allopregnanolone levels in serum and olfactory bulb relative to males. In the repeated cocaine study, females had significantly higher allopregnanolone levels in olfactory bulb, frontal cortex, and serum. Finally, acute cocaine increased allopregnanolone levels in the frontal cortex of females in proestrus, relative to non-proestrus stages. Conclusion: Collectively these results suggest that allopregnanolone levels vary across brain regions and by sex, which may play a part in differential responses to cocaine by sex. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The current study was conducted to assess the effect of HFD (40%) on estrous cycle regularity and body weight in female rats. Fourteen female Wistar albino rats were randomly divided into two groups. The control group (I) received the standard chow diet, and the HFD group (II) received the HFD (55% basal diet, 3% sesame oil, 25% beef tallow, 5% milk powder, 5% roasted peanuts, 5% egg, and 2% NaCl) daily for 10 successive weeks. Bodyweight was recorded every week from the beginning of the study to the end, where, at the 8 th week after dietary exposure, the assessment of the estrous cycle was performed daily for ten successive days using visual assessment and vaginal cytology procedures. The HFD group revealed a statistically higher proportion of rats with an irregular estrous cycle (p = 0.031) and a significantly increased diestrus index vs. the control group (p = 0.025). The HFD group revealed a nonsignificant decrease in the cycle frequency, a significant decrease in the total days of the proestrus stage (p ≤ 0.001), and a nonsignificant shortening in the estrus and metestrus stages vs. control. In contrast, the HFD group revealed a significantly longer diestrus stage than the control group (p = 0.025). Weight gain and body weight were significantly increased throughout the experiment in the HFD group when compared with the control group (p < 0.001). In conclusion, HFD results in increased body weight and increased estrous cycle irregularities, which may impair the female reproductive function. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

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 sameversus 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. [ABSTRACT FROM AUTHOR]

The arcuate nucleus kisspeptin (ARNKISS) neurons represent the GnRH pulse generator that likely drives pulsatile gonadotropin secretion in all mammals. Using an improved GCaMP fiber photometry system enabling long-term continuous recordings, we aimed to establish a definitive profile of ARNKISS neuronal activity across the murine estrous cycle. As noted previously, a substantial reduction in the frequency of ARNKISS neuron synchronization events (SEs) occurs on late proestrus and extends into estrus. The SE amplitude remains constant throughout the cycle. During metestrus, we unexpectedly detected many multipeak SEs where many SEs occurred rapidly, within 160 seconds of each other. By applying a machine learning-based, k-means clustering analysis, we were further able to detect substantial within-stage variability in the patterns of pulse generator activity. Estrous cycle-dependent changes in SE activity occurred around the time of lights on and off. We also find that a mild stressor such as vaginal lavage reduces ARNKISS neuron SE frequency for up to 3 hours. These observations provide a comprehensive account of ARNKISS neuron activity across the estrous cycle, highlight a new pattern of multipeak SE activity, and introduce a new k-means clustering approach for analyzing ARNKISS neuron population behavior. [ABSTRACT FROM AUTHOR]

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 dosedependently 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. [ABSTRACT FROM AUTHOR]

Abstract—Nitric oxide has several important functions in the CNS. This neurotransmitter regulates apoptotic processes, differentiation and proliferation of neurons, synaptic activity and plasticity. Stress during the intrauterine period may be a factor influencing the level of NO in various regions of the CNS. The aim of the study was to investigate the levels of NO metabolites in phylogenetically different structures of the CNS in mature male and female rats at various stages estrous cycle, which were subjected to prenatal stress. Twelve pregnant female rats were exposed to stress on gestation days 16–19 for 3 h in the morning. The NO level was estimated in adult 4-month-old offspring of both sexes. In male rats, the decreased levels of NO metabolites were observed in the cerebellum and hypothalamus whereas in the spinal cord, it was increased. In control females, the levels of NO metabolites were higher in all CNS regions compared to males while after prenatal stress, they changed to a lesser extent. Significant differences were revealed in the spinal cord irrespectively of the estrous cycle and in the cerebellum, at the estrus stage. Finally, regardless of sex, the phylogenetically younger cerebral cortex, was the most resilient to prenatal stress whereas the most pronounced changes were revealed in the phylogenetically ancient region of the CNS such as the spinal cord. Taking into account the importance of NO as a key signaling molecule in the CNS, any changes in its level after prenatal stress may have both adaptive and negative consequences for functional condition of the tissue. [ABSTRACT FROM AUTHOR]

The recurrent hormonal fluctuations within reproductive cycles impact sleep-wake behavior in women and in rats and mice used in preclinical models of sleep research. Strides have been made in sleep-related clinical trials to include equal numbers of women; however, the inclusion of female rodents in neuroscience and sleep research is lacking. Female animals are commonly omitted from studies over concerns of the effect of estrus cycle hormones on measured outcomes. This review highlights the estrous cycle’s broad effects on sleep-wake behavior: from changes in sleep macroarchitecture to regionally specific alterations in neural oscillations. These changes are largely driven by cycle-dependent ovarian hormonal fluctuations occurring during proestrus and estrus that modulate neural circuits regulating sleep-wake behavior. Removal of estrous cycle influence by ovariectomy ablates characteristic sleep changes. Further, sex differences in sleep are present between gonadally intact females and males. Removal of reproductive hormones via gonadectomy in both sexes mitigates some, but not all sex differences. We examine the extent to which reproductive hormones and sex chromosomes contribute to sex differences in sleep-wake behavior. Finally, this review addresses the limitations in our understanding of the estrous cycle’s impact on sleep-wake behavior, gaps in female sleep research that are well studied in males, and the implications that ignoring the estrous cycle has on studies of sleep-related processes.

Abstract Current rodent models of anorexia nervosa (AN) often have accelerated weight loss that often do not allow for investigation of physiological ramifications of prolonged low weight status characteristic of AN. The purpose of this project was to refine a rodent model of AN to extend the duration of low weight status and allow for investigation of recovery. Eight‐week‐old female Sprague Dawley rats underwent 50%–60% food restriction for 30 days. Rats were group‐housed except during feeding, where AN rats were individually housed and given up to 2 h to consume food. Control (CON) rats were allowed to consume food ad libitum. To simulate recovery, a separate cohort of animals underwent the same food restriction protocol for 30 days, then rats (AN‐R) were allowed to consume food ad libitum to facilitate weight recovery for an additional 30 days. AN‐R rats were compared to age matched controls (CON‐R). AN rats lost ~15% bodyweight and were ~30% lighter than CON. Compared to CON, AN rats had ~35% lower fat content, ~18% lower bone mineral density, ~22% smaller plantaris muscle mass and ~52% smaller ovaries. Upon reintroduction of food, AN‐R rats achieved comparable bodyweights to CON‐R rats after ~10 days. However, after 30 days of recovery, AN‐R rats still had ~14% lower bone mineral density and ~11% smaller plantaris mass and ~21% smaller ovaries. This refinement of rodent AN results in physiological side effects of AN without reaching excessive weight loss requiring euthanasia. Moreover, some physiological consequences of simulated AN are not resolved with weight restoration.

Relapse is a major challenge in treating drug addiction, and drug seeking progressively increases after abstinence, a phenomenon termed “incubation of drug craving”. Previous studies demonstrated both sex differences and an effect of estrous cycle in female rats in incubation of cocaine craving. In contrast, while incubation of methamphetamine craving is similar across sexes, whether estrous cycle plays a role in this incubation has yet to be fully addressed. Moreover, whether neural mechanisms underlying incubation of methamphetamine craving differ across estrous cycles is largely unknown. To address these gaps, we first compared methamphetamine self-administration, and methamphetamine seeking on both abstinence days 1 and 28 between male rats and female rats across the estrous cycle. Next, we examined neuronal activation associated with incubated methamphetamine seeking in dorsomedial striatum (DMS) and lateral portion of the anterior intralaminar nucleus of thalamus (AIT-L), two brain areas previously implicated in incubation of methamphetamine craving. We found no effect of sex or estrous cycle on methamphetamine self-administration and methamphetamine seeking on abstinence days 1 and 28. We also found no effect of sex or estrous cycle on the number of Fos-expressing cells in DMS or AIT-L following methamphetamine seeking test. Taken together, our results showed that methamphetamine self-administration and incubation of methamphetamine craving was not dependent on sex or estrous cycles under our experimental condition, and the role of DMS and AIT-L in incubation of methamphetamine craving may be similar across sexes and across estrous cycles in female rats.

Exercise facilitates hippocampal neurogenesis and neuroplasticity that in turn, promotes cognitive function. Our previous studies have demonstrated that in male mice, voluntary exercise enables hippocampus-dependent learning in conditions that are normally subthreshold for long-term memory formation in sedentary animals. Such cognitive enhancement can be maintained long after exercise has ceased and can be re-engaged by a subsequent subthreshold exercise session, suggesting exercise-induced benefits are temporally dynamic. In females, the extent to which the benefits of exercise can be maintained and the mechanisms underlying this maintenance have yet to be defined. Here, we examined the exercise parameters required to initiate and maintain the benefits of exercise in female C57BL/6J mice. Using a subthreshold version of the hippocampus-dependent task called object-location memory (OLM) task, we show that 14d of voluntary exercise enables learning under subthreshold acquisition conditions in female mice. Following the initial exercise, a 7d sedentary delay results in diminished performance, which can be re-facilitated when animals receive 2d of reactivating exercise following the sedentary delay. Assessment of estrous cycle reveals enhanced wheel running activity during the estrus phase relative to the diestrus phase, whereas estrous phase on training or test had no effect on OLM performance. Utilizing the same exercise parameters, we demonstrate that 14d of exercise enhances long-term potentiation (LTP) in the CA1 region of the hippocampus, an effect that persists throughout the sedentary delay and following the reactivating exercise session. Previous studies have proposed exercise-induced BDNF upregulation as the mechanism underlying exercise-mediated benefits on synaptic plasticity and cognition. However, our assessment of hippocampal Bdnf mRNA expression following memory retrieval reveals no difference between exercise conditions and control, suggesting that persistent Bdnf upregulation may not be required for maintenance of exercise-induced benefits. Together, our data indicate that 14d of voluntary exercise can initiate long-lasting benefits on neuroplasticity and cognitive function in female mice, establishing the first evidence on the temporal endurance of exercise-induced benefits in females.

Abstract Background Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. Results For our studies, we employed the preclinical radiotracer [111In]In-FnBPA5, which specifically binds to relaxed fibronectin–an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. Conclusion Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [111In]In-FnBPA5, the matching targeting molecule is in preclinical development.

Abstract 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.

Simple Summary: The golden takin (Budorcas taxicolor bedfordi) is an endangered animal. While information on this species' reproductive physiology is essential for its conservation, endocrinological studies are limited. Monitoring fluctuations in fecal sex steroid hormones is known to be a useful means of understanding reproductive physiological states such as pregnancy and estrus. In this study, we measured the concentrations of sex steroid hormone metabolites excreted in the feces of female golden takins and used the long-term fluctuations to determine their endocrine ovarian activity. This study indicates that the monitoring of fecal sex steroid hormone concentrations can be used to understand estrus and pregnancy and predict delivery. This study investigates the non-invasive monitoring of the endocrine ovarian activities of captive female golden takins (Budorcas taxicolor bedfordi) based on long-term fecal sex steroid hormone metabolite dynamics. Fecal progesterone (P4) metabolite dynamics were monitored in nine females for 0.5–15 years between 2004 and 2022. Fecal estradiol-17β (E2) and estrone (E1) metabolites were measured during certain estrous cycles, and fecal E1 metabolite concentrations were measured during all gestation periods. The breeding season of the captive animals was mainly between May and December, and they were polyestrous animals whose breeding season begins during the long-day period. The onset of the breeding season occurred slightly earlier as age increased. The mean age (±SD) at puberty based on fecal P4 metabolite dynamics was 4.1 ± 2.9 years. The first conception ages ranged from 2.3–10.2 years. The mean estrous cycle period (±SEM) was 25.4 ± 1.1 days, and mounting and mating occurred in periods of low fecal P4 metabolite levels during the breeding season. The mean gestation period (±SD) from the estimated mating date to the calving date was 253.9 ± 5.7 days, and the fecal P4 metabolite distribution during pregnancy was bimodal. Fecal estrone metabolite levels gradually increased 21 weeks before delivery, peaked during the week of delivery, and then markedly decreased in the first week after delivery. Estrus resumed in the first April–August period after delivery (mean ± SD; 103.5 ± 40.9 days) or in May of the year after delivery (421.0 ± 16.5 days). This study revealed that the estrous cycle and pregnancy of female golden takins can be determined by fecal progesterone metabolite dynamics and that fecal estrone metabolite dynamics increases toward parturition and are useful for predicting the date of delivery. This endocrinological information is important for planned breeding efforts for the golden takins. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. Results: For our studies, we employed the preclinical radiotracer [111In]In-FnBPA5, which specifically binds to relaxed fibronectin–an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. Conclusion: Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [111In]In-FnBPA5, the matching targeting molecule is in preclinical development. [ABSTRACT FROM AUTHOR]

Hibernating mammals have annual cycles with strict timing of all processes including reproduction, yet female reproductive physiology is only poorly studied in such species. We investigated the estrous cycle in yellow ground squirrels (Spermophilus fulvus), which hibernate up to 9 months. Using vaginal cytology and serum progesterone and estradiol profiles, we identified proestrus, estrus, metestrus, and anestrus in the cycle. As in other rodents, predominance of cornified cells marked estrus, and an increase in the leukocyte number reflected metestrus. The only estrus in a year started, and then, pregnancy occurred mostly within 3 days after spring emergence. In one female, we noticed a copulatory plug for the first time for this species. The progesterone level increased from proestrus/estrus to pregnancy and decreased in the postlactation period. Estradiol concentration did not change significantly throughout the estrous cycle but varied among females and was consistently high in some of them. The hormone levels did not vary with female age despite smaller body size in yearling females than in older ones. During postlactation, progesterone concentration diminished toward hibernation, and we could not detect signs of prehibernation activation of the female reproductive system. Probably, gonadal preparation in S. fulvus females proceeds at periodic arousals during hibernation. Our data showed fast transitions between phases of the female estrous cycle and early maturation of juvenile females, consistently with the hypothesis of the fast life-history strategy of S. fulvus. [ABSTRACT FROM AUTHOR]

Introduction: The impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitarygonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction. However, whether stress influences reproductive function via modulating PVN CRH or HPA sequelae is not fully elucidated. Methods: In this study, we investigated the impact of chemogenetic activation of PVN CRH neurons on reproductive function. We chronically and selectively stimulated PVN CRH neurons in female CRH-Cre mice using excitatory designer receptor exclusively activated by designer drugs (DREADDs) viral constructs, which were bilaterally injected into the PVN. The agonist compound-21 (C21) was delivered through the drinking water. We determined the effects of DREADDs activation of PVN CRH neurons on the estrous cycles, LH pulse frequency in diestrus and metestrus and LH surge in proestrus mice. The effect of long-term C21 administration on basal corticosterone secretion and the response to acute restraint stress during metestrus was also examined. Additionally, computer simulations of a mathematical model were used to determine the effects of DREADDs activation of PVN CRH neurons, simulating chronic stress, on the physiological parameters examined experimentally. Results: As a result, and consistent with our mathematical model predictions, the length of the estrous cycle was extended, with an increase in the time spent in estrus and metestrus, and a decrease in proestrus and diestrus. Additionally, the frequency of LH pulses during metestrus was decreased, but unaffected during diestrus. The occurrence of the preovulatory LH surge during proestrus was disrupted. The basal level of corticosterone during metestrus was not affected, but the response to acute restraint stress was diminished after long-term C21 application. Discussion: These data suggest that PVN CRH neurons play a functional role in disrupting ovarian cyclicity and the preovulatory LH surge, and that the activity of the GnRH pulse generator remains relatively robust during diestrus but not during metestrus under chronic stress exposure in accordance with our mathematical model predictions. [ABSTRACT FROM AUTHOR]

A series of experiments was designed to evaluate treatment schedules for control of the estrous cycle in which luteolysis is induced prior to atresia of the first follicular wave following a long-term progestin presynchronization treatment in beef heifers. The overarching hypothesis was that the proportion of heifers undergoing luteolysis and expressing estrus following PG administration would be affected by the duration of treatment with an intravaginal progesterone-releasing insert (CIDR; 1.38 g progesterone) and/or by the interval from CIDR removal to prostaglandin F 2ɑ (PG; 500 μg cloprostenol) administration. In each experiment, heifers were blocked by reproductive tract score (RTS) and body weight (BW) and were assigned randomly within block to treatment. In Experiment 1, heifers (n = 91) were assigned to one of four treatments in a 2 x 2 factorial design: presynchronization via CIDR treatment for either 14 d or 18 d with administration of PG either 8 d or 9 d following CIDR removal. In Experiment 2, heifers (n = 63) were assigned to receive administration of PG either 9 d or 10 d following a 14 d CIDR presynchronization. In Experiment 3, heifers (n = 83) were assigned to receive administration of PG either 9 d or 16 d following a 14 d CIDR presynchronization. In Experiment 1, there was a tendency for a greater proportion of heifers to express estrus by 96 h after PG administration when PG administration occurred 9 d versus 8 d after CIDR removal (P = 0.07). Additionally, serum estradiol (E 2) concentrations were greater at the time of PG administration when PG was administered 9 d versus 8 d after CIDR removal following an 18 d CIDR treatment (P = 0.006). In Experiment 2, pregnancy rate to AI (P/AI) was greater among heifers receiving PG administration 9 d versus 10 d after CIDR removal (P = 0.03). There was a tendency for largest follicle diameter (LFD) to be greater among non-estrous heifers receiving PG administration 10 d versus 9 d after CIDR removal when measured at timed AI (P < 0.08). In Experiment 3, there was a tendency for serum progesterone (P 4) concentrations at the time of PG administration to be greater among heifers receiving PG administration 16 d versus 9 d after CIDR removal (P = 0.07). These results provide a preliminary evaluation of the feasibility of inducing luteolysis prior to atresia of the first follicular wave following long-term progestin presynchronization. [Display omitted] • Shorter intervals to PG administration following progestin presynchronization were evaluated. • Inducing luteolysis prior to atresia of the first follicular wave may be feasible. • Shorter interval to PG could reduce pregnancy rates if some CL are not responsive. [ABSTRACT FROM AUTHOR]