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BioRxiv : the Preprint Server For... May 2024Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males....
BACKGROUND
Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine.
METHODS
We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects.
RESULTS
Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus.
CONCLUSIONS
These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.
PubMed: 38826392
DOI: 10.1101/2024.05.20.595049 -
Scientific Reports May 2024Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate...
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.
Topics: Animals; Male; Female; Dendritic Spines; Mice; Estrous Cycle; CA2 Region, Hippocampal; Sex Characteristics; Neurons
PubMed: 38806649
DOI: 10.1038/s41598-024-62951-x -
International Journal of Molecular... May 2024Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent...
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
Topics: Animals; Adrenal Hyperplasia, Congenital; Disease Models, Animal; Steroid 21-Hydroxylase; Mice; Female; Male; Humans; Corticosterone; Aldosterone; Adrenal Glands; Mutation; Progesterone
PubMed: 38791102
DOI: 10.3390/ijms25105062 -
Genes May 2024Insulin receptor signaling promotes cell differentiation, proliferation, and growth which are essential for oocyte maturation, embryo implantation, endometrial...
Insulin receptor signaling promotes cell differentiation, proliferation, and growth which are essential for oocyte maturation, embryo implantation, endometrial decidualization, and placentation. The dysregulation of insulin signaling in women with metabolic syndromes including diabetes exhibits poor pregnancy outcomes that are poorly understood. We utilized the Cre/LoxP system to target the tissue-specific conditional ablation of insulin receptor () and insulin-like growth factor-1 receptor () using an anti-Mullerian hormone receptor 2 () Cre-driver which is active in ovarian granulosa and uterine stromal cells. Our long-term goal is to examine insulin-dependent molecular mechanisms that underlie diabetic pregnancy complications, and our conditional knockout models allow for such investigation without confounding effects of ligand identity, source and cross-reactivity, or global metabolic status within dams. Puberty occurred with normal timing in all conditional knockout models. Estrous cycles progressed normally in females but were briefly stalled in diestrus in and double receptor (DKO) mice. The expression of vital ovulatory genes (, , ) was not significantly different in 12 h post-hCG superovulated ovaries in knockout mice. Antral follicles exhibited an elevated apoptosis of granulosa cells in and DKO mice. However, the distribution of ovarian follicle subtypes and subsequent ovulations was normal in all insulin receptor mutants compared to littermate controls. While ovulation was normal, all knockout lines were subfertile suggesting that the loss of insulin receptor signaling in the uterine stroma elicits implantation and decidualization defects responsible for subfertility in -Cre-derived insulin receptor mutants.
Topics: Animals; Female; Receptor, Insulin; Receptor, IGF Type 1; Mice; Ovary; Mice, Knockout; Infertility, Female; Ovulation; Granulosa Cells; Pregnancy; Signal Transduction
PubMed: 38790245
DOI: 10.3390/genes15050616 -
Animal Reproduction 2024As a positional and geometrical isomer of linoleic acid, trans 10, cis 12 conjugated linoleic acid (t10c12-CLA) reduces white fat by reducing food intake, modulating...
As a positional and geometrical isomer of linoleic acid, trans 10, cis 12 conjugated linoleic acid (t10c12-CLA) reduces white fat by reducing food intake, modulating lipid metabolism, and stimulating energy expenditure. However, the t10c12-CLA products are mostly mixtures, making it difficult to obtain accurate results. Studies are needed to investigate the effects of pure t10c12-CLA on animals and humans. In this study, we used the biallelic transgenic (tg) mice, which could produce t10c12-CLA itself, to investigate the effects of pure t10c12-CLA on female reproductive ability. The results showed that the body and relative ovary weights had no significant difference between tg and wild-type (wt) littermates at ages 3 or 10 weeks. While the fecundity test found that tg mice had a significantly longer first litter time (32.0 ± 4.70 days vs. 21.3 ± 2.31 days, <0.05), and a significantly lower number of litters (4.75 ± 2.75 vs. 6.67 ± 0.57, <0.05) when compared with wt mice during continuous mating within seven months. Hormone profiles showed that serum estradiol levels did not change in tg mice; however, significantly (<0.05) decreased progesterone and increased prostaglandin E2 levels were observed in tg mice compared with those of wt mice. Hematoxylin-eosin staining showed no pathological characteristics in tg ovaries, except for the increased atresia follicles (<0.05). Moreover, the tg mice had a significantly more extended diestrus period than the wt mice (48.4 ± 6.38% vs. 39.6 ± 3.81%, <0.05). In summary, t10c12-CLA could affect serum progesterone and prostaglandin E2 levels, lead to a disordered estrus cycle, and impact the reproductive performance of female mice. This study provided theoretical and biosafety recommendations for applying t10c12-CLA in female mammals.
PubMed: 38756621
DOI: 10.1590/1984-3143-AR2024-0010 -
Biology of Reproduction Jun 2024Uterine muscle contractility is essential for reproductive processes including sperm and embryo transport, and during the uterine cycle to remove menstrual effluent....
Uterine muscle contractility is essential for reproductive processes including sperm and embryo transport, and during the uterine cycle to remove menstrual effluent. Even still, uterine contractions have primarily been studied in the context of preterm labor. This is partly due to a lack of methods for studying the uterine muscle contractility in the intact organ. Here, we describe an imaging-based method to evaluate mouse uterine contractility of both the longitudinal and circular muscles in the cycling stages and in early pregnancy. By transforming the image-based data into three-dimensional spatiotemporal contractility maps, we calculate waveform characteristics of muscle contractions, including amplitude, frequency, wavelength, and velocity. We report that the native organ is highly contractile during the progesterone-dominant diestrus stage of the cycle when compared to the estrogen-dominant proestrus and estrus stages. We also observed that during the first phase of uterine embryo movement when clustered embryos move toward the middle of the uterine horn, contractions are dynamic and non-uniform between different segments of the uterine horn. In the second phase of embryo movement, contractions are more uniform and rhythmic throughout the uterine horn. Finally, in Lpar3-/- uteri, which display faster embryo movement, we observe global and regional increases in contractility. Our method provides a means to understand the wave characteristics of uterine smooth muscle in response to modulators and in genetic mutants. Better understanding uterine contractility in the early pregnancy stages is critical for the advancement of artificial reproductive technologies and a possibility of modulating embryo movement during clinical embryo transfers.
Topics: Female; Animals; Uterine Contraction; Pregnancy; Mice; Uterus; Estrous Cycle
PubMed: 38713674
DOI: 10.1093/biolre/ioae071 -
Heliyon Apr 2024Social isolation can cause serious problem in performance of individuals in community. As gender differences may cause variation results in the severity of depressive...
The role of gender differences in the outcome of juvenile social isolation: Emphasis on changes in behavioral, biochemical and expression of nitric oxide synthase genes alteration.
Social isolation can cause serious problem in performance of individuals in community. As gender differences may cause variation results in the severity of depressive behavior and response of patients to therapy, the impact of gender and the interaction of the level of endocrine secretion in depression were investigated in this study. Wistar rats of both sexes were subjected to post-weaning social isolation (PWSI) conditions and, together with the control group, experienced several behavioral tests including open-field Test (OFT), elevated plus maze (EPM), force swimming test (FST), splash test and novel object recognition test (NOR). Hippocampal tissue was isolated to measure biochemical factors such as nitric oxide level, FRAP amount, MDA level. In addition, real-time-PCR test was used to quantify the genes expression level of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). On the other hand, sexual hormone levels in blood were measured. Both cognitive and behavioral f unctions were declined as the result of PWSI induction in male and diestrus female rats. The consequent surge of estradiol during estrous phase seems to suppress the accumulation of reactive oxygen species (ROS), and modulate iNOS and nNOS expression. In conclusion, while the pattern of PWSI in surge cellular antioxidants, raising cellular ROS level is gender-specific, this alleviation was in relation with the drop of estradiol and unrelated with testosterone level.
PubMed: 38617928
DOI: 10.1016/j.heliyon.2024.e28964 -
BioRxiv : the Preprint Server For... Apr 2024Food intake varies across the stages of a rat's estrous cycle. It is reasonable to hypothesize that this cyclic fluctuation in consumption reflects an impact of hormones...
UNLABELLED
Food intake varies across the stages of a rat's estrous cycle. It is reasonable to hypothesize that this cyclic fluctuation in consumption reflects an impact of hormones on taste palatability/preference, but evidence for this hypothesis has been mixed, and critical within-subject experiments in which rats sample multiple tastes during each of the four main estrous phases (metestrus, diestrus, proestrus, and estrus) have been scarce. Here, we assayed licking for pleasant (sucrose, NaCl, saccharin) and aversive (quinine-HCl, citric acid) tastes each day for 5-10 days while tracking rats' estrous cycles through vaginal cytology. Initial analyses confirmed the previously-described increased consumption of pleasant stimuli 24-48 hours following the time of high estradiol. A closer look, however, revealed this effect to reflect a general magnification of palatability-higher than normal preferences for pleasant tastes and lower than normal preferences for aversive tastes-during metestrus. We hypothesized that this phenomenon might be related to estradiol processing in the lateral hypothalamus (LH), and tested this hypothesis by inhibiting LH estrogen receptor activity with ICI during tasting. Control infusions replicated the metestrus magnification of palatability pattern; ICI infusions blocked this effect as predicted, but failed to render preferences "cycle free," instead delaying the palatability magnification until diestrus. Clearly, estrous phase mediates details of taste palatability in a manner involving hypothalamic actions of estradiol; further work will be needed to explain the lack of a flat response across the cycle with hypothalamic estradiol binding inhibited, a result which perhaps suggests dynamic interplay between brain regions or hormones.
SIGNIFICANCE STATEMENT
Consummatory behaviors are impacted by many variables, including naturally circulating hormones. While it is clear that consumption is particularly high during the stages following the high-estradiol stage of the rodent's estrous (and human menstrual) cycle, it is as of yet unclear whether this phenomenon reflects cycle stage-specific palatability (i.e., whether pleasant tastes are particularly delicious, and aversive tastes particularly disgusting, at particular phases). Here we show that palatability is indeed modulated by estrous phase, and that this effect is governed, at least in part, by the action of estradiol within the lateral hypothalamus. These findings shed light on the mechanisms underlying the adverse impact on human welfare due to irregularities observed across the otherwise cyclic menstrual process.
PubMed: 38617267
DOI: 10.1101/2024.04.01.587593 -
PloS One 2024During the oestrous cycle, the bovine endometrium undergoes morphological and functional changes, which are regulated by alterations in the levels of oestrogen and...
During the oestrous cycle, the bovine endometrium undergoes morphological and functional changes, which are regulated by alterations in the levels of oestrogen and progesterone and consequent changes in gene expression. To clarify these changes before and after oestrus, RNA-seq was used to profile the transcriptome of oestrus-synchronized beef heifers. Endometrial samples were collected from 29 animals, which were slaughtered in six groups beginning 12 h after the withdrawal of intravaginal progesterone releasing devices until seven days post-oestrus onset (luteal phase). The groups represented proestrus, early oestrus, metoestrus and early dioestrus (luteal phase). Changes in gene expression were estimated relative to gene expression at oestrus. Ingenuity Pathway Analysis (IPA) was used to identify canonical pathways and functional processes of biological importance. A total of 5,845 differentially expressed genes (DEGs) were identified. The lowest number of DEGs was observed at the 12 h post-oestrus time point, whereas the greatest number was observed at Day 7 post-oestrus onset (luteal phase). A total of 2,748 DEGs at this time point did not overlap with any other time points. Prior to oestrus, Neurological disease and Organismal injury and abnormalities appeared among the top IPA diseases and functions categories, with upregulation of genes involved in neurogenesis. Lipid metabolism was upregulated before oestrus and downregulated at 48h post-oestrus, at which point an upregulation of immune-related pathways was observed. In contrast, in the luteal phase the Lipid metabolism and Small molecule biochemistry pathways were upregulated.
Topics: Cattle; Animals; Female; Progesterone; Estrus; Endometrium; Gene Expression Profiling; Transcriptome
PubMed: 38547106
DOI: 10.1371/journal.pone.0301005 -
Animals : An Open Access Journal From... Mar 2024Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. This narrative review aims to provide relevant... (Review)
Review
Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. This narrative review aims to provide relevant detailed information on (1) the canine estrus cycle and its impact on canine diabetes mellitus (CDM) etiology and management, (2) the role of pyometra as a further cause of insulin resistance, and (3) useful individual therapeutic and preventive strategies. PRDM is recognized due to diestrus, exogenous progestogen exposure, pregnancy, and P4-production ovarian dysfunction. Pyometra represents additional inflammatory and septic negative influence on insulin sensitivity, and its diagnosis associated with CDM is therapeutically challenging. The estrus cycle's hormone fluctuations seem to modulate peripheric insulin sensibility by influencing insulin receptor (IR) affinity and its binding capacity, as well as modulating tyrosine kinase activity. Pyometra was shown to negatively influence IR compensatory mechanisms to insulin resistance causing glucose intolerance. Spaying and pregnancy termination may cause diabetes remission in PRDM cases in a median time of 10 days (1-51). Pharmacological annulment of progesterone effects may benefit patients unable to undergo surgery; however, remission chances are virtually null. The ALIVE (Agreeing Language in Veterinary Endocrinology) project proposed new criteria for CDM diagnoses and subclinical diabetes recognition. These new concepts may increase the frequency of a PRDM diagnosis and, even more, its relevance. Spaying represents a preventive measure against pyometra and PRDM that should be individually assessed in light of its recognized benefits and harms.
PubMed: 38539988
DOI: 10.3390/ani14060890